U.S. patent application number 15/039650 was filed with the patent office on 2017-06-15 for piperidine derivatives for use in the treatment or prevention of psychiatric and neurological conditions.
The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to Anne Goldby, Kerry Jenkins, Martin Teall.
Application Number | 20170166553 15/039650 |
Document ID | / |
Family ID | 49918264 |
Filed Date | 2017-06-15 |
United States Patent
Application |
20170166553 |
Kind Code |
A1 |
Goldby; Anne ; et
al. |
June 15, 2017 |
Piperidine Derivatives for Use in the Treatment or Prevention of
Psychiatric and Neurological Conditions
Abstract
The present invention provides compounds of formula (I) and
pharmaceutically acceptable salts thereof, in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in the
specification, processes for their preparation, pharmaceutical
compositions containing them and their use in therapy.
##STR00001##
Inventors: |
Goldby; Anne; (Cambridge,
GB) ; Jenkins; Kerry; (Cambridge, GB) ; Teall;
Martin; (Cambridge, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka |
|
JP |
|
|
Family ID: |
49918264 |
Appl. No.: |
15/039650 |
Filed: |
November 26, 2014 |
PCT Filed: |
November 26, 2014 |
PCT NO: |
PCT/GB2014/053499 |
371 Date: |
May 26, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 43/00 20180101; A61P 29/00 20180101; C07D 401/14 20130101;
A61P 1/04 20180101; C07D 401/04 20130101; A61P 25/18 20180101; A61P
25/04 20180101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 401/04 20060101 C07D401/04 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 2013 |
GB |
1320905.1 |
Claims
1.-16. (canceled)
17. A compound of formula ##STR00110## wherein R.sup.1 represents a
6- to 10-membered heteroaromatic group containing from one to three
ring heteroatoms selected from nitrogen atoms, the heteroaromatic
group being substituted by at least one substituent selected from
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylcarbonyloxy,
C.sub.1-C.sub.6 alkoxycarbonyl, --NR.sup.6R.sup.7,
--CONR.sup.8R.sup.9, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyloxy or C.sub.3-C.sub.6 cycloalkylmethyl; either R.sup.2
represents a hydrogen or fluorine atom or a hydroxyl or
C.sub.1-C.sub.3 alkoxy group, R.sup.3 represents a hydrogen atom
and R.sup.4 represents a hydrogen atom, or, when R.sup.4 represents
a hydrogen atom, R.sup.2 may together with R.sup.3 form a
carbon-carbon single bond or R.sup.2 and R.sup.3 may together with
the carbon atoms to which they are attached form a cyclopropyl
ring, or, when R.sup.3 represents a hydrogen atom, R.sup.2 may
together with R.sup.4 form a carbon-carbon single bond or R.sup.2
and R.sup.4 may together with the carbon atoms to which they are
attached form a cyclopropyl ring; R.sup.5 represents a 5- to
6-membered heteroaromatic group containing from one to three ring
heteroatoms selected from nitrogen atoms, the heteroaromatic group
being substituted by at least one substituent selected from
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylcarbonyloxy,
C.sub.1-C.sub.6 alkoxycarbonyl, --NR.sup.10R.sup.11,
--CONR.sup.12R.sup.13, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyloxy or C.sub.3-C.sub.6 cycloalkylmethyl; R.sup.6 and
R.sup.7 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl group, or
R.sup.6 and R.sup.7 may together with the nitrogen atom to which
they are attached form a 4- to 7-membered saturated heterocyclic
ring optionally substituted by at least one substituent selected
from fluorine, hydroxyl and C.sub.1-C.sub.3 alkoxy; R.sup.8 and
R.sup.9 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group, or R.sup.8 and R.sup.9 may together
with the nitrogen atom to which they are attached form a 4- to
7-membered saturated heterocyclic ring; R.sup.10 and R.sup.11 each
independently represent a hydrogen atom or a hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy or C.sub.3-C.sub.6 cycloalkyl group, or R.sup.10 and
R.sup.11 may together with the nitrogen atom to which they are
attached form a 4- to 7-membered saturated heterocyclic ring
optionally substituted by at least one substituent selected from
fluorine, hydroxyl and C.sub.1-C.sub.3 alkoxy; and R.sup.12 and
R.sup.13 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group, or R.sup.12 and R.sup.13may together
with the nitrogen atom to which they are attached form a 4- to
7-membered saturated heterocyclic ring; provided that the compound
of formula (I) is not: (1)
[4-[3-(7-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]py-
ridin-2-amine], (2)
[N-methyl-4-[3-(7-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]py-
ridin-2-amine, (3)
[3-[3-[(1,1-dimethylethyl)amino)imidazo[1,2-a]pyridin-2-yl]-1-piperidinyl-
](3-methyl-4-pyridinyl) methanone, (4)
[3-[3-[(1,1-dimethylethyl)amino)imidazo[1,2-a]pyridin-2-yl]-1-piperidinyl-
](2-methoxy-4-pyridinyl) methanone, (5)
[2-(methylamino)-4-pyridinyl][3-[1-(1-methylethyl)-1H-benzimidazol-2-yl]--
1-piperidinyl] methanone, (6) (1,5-dimethyl-1H-pyrazol-4-yl)
[3-(6-methyl-1H-benzimidazol-2-yl)-1-piperidinyl]methanone, (7)
6-{1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]-3-piperidinyl}-N,N-dimethyl-
nicotinamide, (8) (1-methyl-1H-pyrazol-4-yl)
[3-(5-methyl-2-pyridinyl)-1-piperidinyl]methanone (CAS No.
1380857-90-8), or (9)
[3-[6-(methylamino)-2-pyridinyl]-1-piperidinyl](1-methyl-1H-pyrazo-
l-4-yl)methanone; or a pharmaceutically acceptable salt
thereof.
18. The compound according to claim 17, wherein, in R.sup.1, the
heteroaromatic group is 6- to 9-membered.
19. The compound according to claim 17, wherein, in R.sup.1, the
heteroaromatic group is selected from pyridinyl, benzodiazolyl and
indolyl.
20. The compound according to claim 17, wherein, in R.sup.1, the
heteroaromatic group is substituted by one or two substituents
independently selected from halogen, C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.2 haloalkyl.
21. The compound according to claim 17, in which R.sup.2 represents
a hydrogen atom.
22. The compound according to claim 17, in which R.sup.2 represents
a C.sub.1-C.sub.3 alkoxy group.
23. The compound according to claim 17, in which R.sup.2 represents
a fluorine atom.
24. The compound according to claim 17, wherein, in R.sup.5, the
heteroaromatic group is selected from pyridinyl, pyridazinyl and
pyrazolyl.
25. The compound according to claim 17, wherein, in R.sup.5, the
heteroaromatic group is substituted by at least one substituent
selected from halogen, C.sub.1-C.sub.2 alkyl and
--NR.sup.10R.sup.11.
26. The compound according to claim 17, wherein R.sup.10 and
R.sup.11 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group.
27. The compound according to claim 17 being selected from:
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-ca-
rbonyl}pyridin-2-amine,
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-c-
arbonyl}pyridin-2-amine (Enantiomer 1 substantially as hereinbefore
described and with reference to Example 2),
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-c-
arbonyl}pyridin-2-amine (Enantiomer 2 substantially as hereinbefore
described and with reference to Example 3),
N,N-Dimethyl-4-[3-(1-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl-
]pyridin-2-amine,
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,-
3-benzodiazole,
N-Methyl-5-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbo-
nyl}pyridazin-3-amine,
2-[1-(1-Ethyl-1H-pyrazole-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1-
,3-benzodiazole,
N,N-Dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine,
N-Methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyrida-
zin-3-amine,
4-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridin-2--
amine,
5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyri-
dazin-3-amine,
5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-am-
ine,
N,N-Dimethyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbony-
l}pyridazin-3-amine,
N-Methyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl
}pyridazin-3-amine,
2-{1-[(1-Ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-1-(propan-2-yl)-1-
H-indole,
1-Methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-carbonyl-
}-1H-pyrazol-3-amine,
1-Ethyl-2-{1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-5-methyl--
1H-indole,
5-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-m-
ethylpyridazin-3-amine,
5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrid-
azin-3-amine,
5-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrid-
azin-3-amine,
5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylp-
yridazin-3-amine,
5-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylp-
yridazin-3-amine,
N-Methyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine,
N,N-Dimethyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyri-
dazin-3-amine,
4-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine,
4-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine,
4-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine,
5-[3-(5-Chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]-N,N-dimethylpy-
ridazin-3-amine,
4-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-car-
bonyl}-N-methylpyridin-2-amine,
5-({3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidin-1-yl}-
carbonyl)-N-methylpyridazin-3-amine,
5-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-car-
bonyl}-N,N-dimethylpyridazin-3-amine,
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-
-(trifluoromethyl)pyridine,
4-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-car-
bonyl}-N,N-dimethylpyridin-2-amine,
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-me-
thylpyridin-2-amine,
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-met-
hylpyridin-2-amine,
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-me-
thylpyridazin-3-amine,
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N,N--
dimethylpyridazin-3-amine,
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-met-
hylpyridazin-3-amine,
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N,N-d-
imethylpyridazin-3-amine,
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-
-methylpyridine,
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-fluoropiperidin-3-yl]-3--
methylpyridine,
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-me-
thyl-1H-pyrazol-3-amine,
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1-met-
hyl-1H-pyrazol-3-amine, and pharmaceutically acceptable salts
thereof.
28. A process for the preparation of a compound of formula (I) as
defined in claim 17 or a pharmaceutically acceptable salt thereof
which comprises reacting a compound of formula ##STR00111## wherein
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in formula (I)
or a salt thereof, with a compound of formula ##STR00112## wherein
R.sup.5 is as defined in formula (I); and optionally thereafter
carrying out one or more of the following procedures: removing any
protecting groups converting a compound of formula (I) into another
compound of formula (I) forming a pharmaceutically acceptable
salt.
29. A pharmaceutical composition comprising a compound of formula
(I) or a pharmaceutically acceptable salt thereof according to
claim 17 in association with a pharmaceutically acceptable
adjuvant, diluent or carrier, and optionally one or more other
therapeutic agents.
30. A method of treating an inflammatory bowel disease or irritable
bowel syndrome, comprising administering to an individual in need
thereof a therapeutically effective amount of a compound of formula
(I) or a pharmaceutically acceptable salt thereof as claimed in
claim 17.
31. A method of treating schizophrenia, schizophreniform disorder,
schizoaffective disorder, cognitive disorders or pain, comprising
administering to an individual in need thereof a therapeutically
effective amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof as claimed in claim 17.
32. An intermediate of formula (II) as defined in claim 28.
Description
[0001] The present invention relates to the use of piperidine
derivatives in therapy, particularly for the treatment or
prevention of psychiatric and neurological conditions.
[0002] Prokineticins are cysteine-rich regulatory peptides that are
thought to exert signaling activity via two highly conserved G
protein-coupled receptors (GPCR), the prokineticin receptor 1 (PKR1
or PROKR1) and the prokineticin receptor 2 (PKR2 or PROKR2), that
belong to the 7-transmembrane domain, G protein-coupled receptor
(GPCR) superfamily.
[0003] Prokineticin receptor 1 (also known as GPR73) shows 87%
homology to Prokineticin Receptor 2 (also known as GPR73L1).
Prokineticins (PK1 and PK2) contain 86 and 81 amino acids
respectively, sharing 45% amino acid identity. Both prokineticins
activate the two prokineticin receptors, PKR1 and PKR2, with
similar potency.
[0004] PKR1 receptors couple to G.sub.q/G.sub.11 proteins leading
to phospholipase C activation, inositol phosphate production and
calcium mobilization. In addition, activation of the
mitogen-activated protein kinase (MAPK) pathways has also been
described.
[0005] PKR1 is broadly distributed throughout peripheral tissues
including the intestinal tract, testis, uterus, lung, mouse dorsal
root ganglia, macrophage, bone, heart, rectum, white adipose and
peripheral blood leukocytes. In addition, the receptor is expressed
in the brain particularly in olfactory regions as well as in dorsal
root ganglion (DRG) neurons, mouse hippocampus, dentate gyms,
cerebellar cortex, cerebral cortex, human hippocampus, amygdala,
medulla oblongata and spinal cord.
[0006] Prokineticins were originally identified as potent agents
mediating gut motility, but were later shown to promote
angiogenesis in steroidogenic glands (e.g. adrenal gland), heart
and reproductive systems. They also modulate neurogenesis,
circadian rhythms, nociception, haematopoiesis as well as the
immune response. Prokineticins are thought to be associated with
pathologies of the reproductive and nervous systems, myocardial
infarction and tumorigenesis.
[0007] Consequently, antagonisim of the functions of the
prokineticins may have utility in the treatment of disorders or
diseases including gastrointestinal motility, angiogenesis,
hematopoiesis, diabetes (e.g. as described in International Patent
Application Publication No. WO 2010/077976) and pain (e.g. as
described in International Patent Application Publication No. WO
2007/079214).
[0008] Certain piperidine derivatives are known chemical library
compounds with no known use that are available from commercial
suppliers such as Chembridge Corporation, Asinex Limited or Aurora
Fine Chemicals, in particular the following compounds having
Chemical Abstracts Registry Nos. 1394453-66-7, 1394435-52-9,
1381674-37-8, 1381666-19-8, 1214443-17-0, 1428016-79-8,
1381044-09-2, 1380857-90-8 and 1380854-82-9. Other piperidine
derivatives which are said to be effective as metabotropic
glutamate receptor (mGluR) modulators are known from International
Patent Application Publication No. WO 2008/015271.
[0009] We have now discovered a new class of compounds that are
prokineticin receptor modulators which have desirable activity
profiles. The compounds of this invention have beneficial potency,
selectivity and/or pharmacokinetic properties.
[0010] In accordance with the present invention, there is therefore
provided a compound of formula
##STR00002##
[0011] wherein [0012] R.sup.1 represents a 6- to 10-membered
heteroaromatic group containing from one to three ring heteroatoms
selected from nitrogen atoms, the heteroaromatic group being
substituted by at least one substituent selected from halogen,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylcarbonyloxy,
C.sub.1-C.sub.6 alkoxycarbonyl, --NR.sup.6R.sup.7,
--CONR.sup.8R.sup.9, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyloxy or C.sub.3-C.sub.6 cycloalkylmethyl; [0013] either
R.sup.2 represents a hydrogen or fluorine atom or a hydroxyl or
C.sub.1-C.sub.3 alkoxy group, R.sup.3 represents a hydrogen atom
and R.sup.4 represents a hydrogen atom, or, when R.sup.4 represents
a hydrogen atom, R.sup.2 may together with R.sup.3 form a
carbon-carbon single bond or R.sup.2 and R.sup.3 may together with
the carbon atoms to which they are attached form a cyclopropyl
ring, or, when R.sup.3 represents a hydrogen atom, R.sup.2 may
together with R.sup.4 form a carbon-carbon single bond or R.sup.2
and R.sup.4 may together with the carbon atoms to which they are
attached form a cyclopropyl ring; [0014] R.sup.5 represents a 5- to
6-membered heteroaromatic group containing from one to three ring
heteroatoms selected from nitrogen atoms, the heteroaromatic group
being substituted by at least one substituent selected from
halogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylcarbonyloxy,
C.sub.1-C.sub.6 alkoxycarbonyl, --NR.sup.10R.sup.11,
--CONR.sup.12R.sup.13, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyloxy or C.sub.3-C.sub.6 cycloalkylmethyl; [0015] R.sup.6
.sub.and R.sup.7 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl group, or
R.sup.6 and R.sup.7may together with the nitrogen atom to which
they are attached form a 4- to 7-membered saturated heterocyclic
ring optionally substituted by at least one substituent selected
from fluorine, hydroxyl and C.sub.1-C.sub.3 alkoxy; [0016] R.sup.8
.sub.and R.sup.9 each independently represent a hydrogen atom or a
C.sub.1-C.sub.6 alkyl group, or R.sup.8 and R.sup.9may together
with the nitrogen atom to which they are attached form a 4- to
7-membered saturated heterocyclic ring; [0017] R.sup.10 and
R.sup.11 each independently represent a hydrogen atom or a
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkoxy or C.sub.3-C.sub.6 cycloalkyl group, or
R.sup.10 and R.sup.11may together with the nitrogen atom to which
they are attached form a 4- to 7-membered saturated heterocyclic
ring optionally substituted by at least one substituent selected
from fluorine, hydroxyl and C.sub.1-C.sub.3 alkoxy; and [0018]
R.sup.12 .sub.and R.sup.13 each independently represent a hydrogen
atom or a C.sub.1-C.sub.6 alkyl group, or R.sup.12 and R.sup.13 may
together with the nitrogen atom to which they are attached form a
4- to 7-membered saturated heterocyclic ring;
[0019] provided that the compound of formula (I) is not: [0020] (1)
[4-[3-(7-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]pyridin-2-a-
mine] (CAS No. 1394453-66-7), [0021] (2)
[N-methyl-4-[3-(7-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]py-
ridin-2-amine (CAS No. 1394435-52-9), [0022] (3)
[3-[3-[(1,1-dimethylethyl)amino)imidazo[1,2-a]pyridin-2-yl]-1-piperidinyl-
](3-methyl-4-pyridinyl)methanone (CAS No. 1381674-37-8), [0023] (4)
[3-[3-[(1,1-dimethylethyl)amino)imidazo[1,2-a]pyridin-2-yl]-1-piperidinyl-
](2-methoxy-4-pyridinyl)methanone (CAS No. 1381666-19-8), [0024]
(5)
[2-(methylamino)-4-pyridinyl][3-[1-(1-methylethyl)-1H-benzimidazol-2-yl]--
1-piperidinyl]methanone (CAS No. 1214443-17-0), [0025] (6)
(1,5-dimethyl-1H-pyrazol-4-yl)[3-(6-methyl-1H-benzimidazol-2-yl)-1-piperi-
dinyl]methanone (CAS No. 1428016-79-8), [0026] (7)
6-{1-[(1,3-dimethyl-1H-pyrazol-4-yl)carbonyl]-3-piperidinyl}-N,N-dimethyl-
nicotinamide (CAS No. 1381044-09-2), [0027] (8)
(1-methyl-1H-pyrazol-4-yl)[3-(5-methyl-2-pyridinyl)-1-piperidinyl]methano-
ne (CAS No. 1380857-90-8), or [0028] (9)
[3-[6-(methylamino)-2-pyridinyl]-1-piperidinyl](1-methyl-1H-pyrazol-4-yl)-
methanone (CAS No. 1380854-82-9); or a pharmaceutically acceptable
salt thereof.
[0029] In the context of the present specification, unless
otherwise stated, an alkyl, alkenyl or alkynyl substituent group or
an alkyl, alkenyl or alkynyl moiety in a substituent group may be
linear or branched. Examples of C.sub.1-C.sub.6 alkyl
groups/moieties include methyl, ethyl, propyl, 2-methyl-1-propyl,
2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl,
2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl,
3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,
3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,
3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl,
tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. Examples of
C.sub.2-C.sub.6 alkenyl groups/moieties include ethenyl, propenyl,
1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl,
1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl. Examples of
C.sub.2-C.sub.6 alkynyl groups/moieties include ethynyl, propynyl,
1-butynyl, 2-butynyl, 1-pentynyl and 1-hexynyl.
[0030] A C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 haloalkoxy
substituent group/moiety will comprise at least one halogen atom,
e.g. one, two, three, four or five halogen atoms, examples of which
include trifluoromethyl, trifluoromethoxy or pentafluoroethyl.
[0031] A C.sub.1-C.sub.6 hydroxyalkyl substituent group/moiety will
comprise at least one hydroxyl group, e.g. one, two, three or four
hydroxyl groups, examples of which include --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CH.sub.2OH,
--CH(OH)CH.sub.2OH, --CH(CH.sub.3)OH and
--CH(CH.sub.2OH).sub.2.
[0032] The term "heteroaromatic" group, as it is used herein,
refers to an aryl group in which from 1 to 3 ring carbon atoms are
replaced by nitrogen atoms. The heteroaromatic group may be
monocyclic or polycyclic (e.g. bicyclic) in which the two or more
rings are fused. The heteroaromatic group can be bonded at any
suitable ring atom (i.e. at any carbon or nitrogen atom of the
heteroaromatic ring system). Examples of heteroaromatic groups
include the following:
##STR00003##
[0033] A C.sub.3-C.sub.6 cycloalkyl group or moiety in a
substituent group represents a saturated monocyclic hydrocarbon
ring structure containing from three to six carbon atoms.
[0034] A 4- to 7-membered saturated heterocyclic ring will contain
at least one ring nitrogen atom and may contain one or more (e.g.
one or two) further ring heteroatoms independently selected from
nitrogen, oxygen and sulphur atoms. It will be understood that the
definition is not intended to include unstable structures or any
O--O, O--S or S--S bonds and that a substituent, if present, may be
attached to any suitable ring atom. Examples of heterocyclic rings
include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, 1,4-azathianyl, azepanyl and 1,4-oxaazepanyl.
[0035] When any chemical moiety or group in formula (I) is
described as being optionally substituted, it will be appreciated
that the moiety or group may be either unsubstituted or substituted
by one or more of the specified substituents. It will be
appreciated that the number and nature of substituents will be
selected so as to avoid sterically undesirable combinations.
[0036] R.sup.1 represents a 6-, 7- or 8- to 9- or 10-membered
heteroaromatic group containing one, two or three ring heteroatoms
selected from nitrogen atoms (e.g. pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, triazinyl, benzodiazolyl, indolyl,
quinolinyl and quinazolinyl), the heteroaromatic group being
substituted by at least one substituent (e.g. one, two, three or
four substituents independently) selected from halogen (e.g.
fluorine, chlorine or bromine), cyano, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkyl, C.sub.2-C.sub.6 or
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.6 or C.sub.2-C.sub.4
alkynyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or C.sub.1-C.sub.2
haloalkyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or C.sub.1-C.sub.2
hydroxyalkyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 alkoxy, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 haloalkoxy, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 alkylcarbonyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4,
or C.sub.1-C.sub.2 alkylcarbonyloxy, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkoxycarbonyl,
--NR.sup.6R.sup.7, --CONR.sup.8R.sup.9, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 cycloalkyloxy or C.sub.3-C.sub.6
cycloalkylmethyl.
[0037] In an embodiment of the invention, R.sup.1 represents a 6-
to 7-, 8- or 9-membered heteroaromatic group containing one, two or
three ring heteroatoms selected from nitrogen atoms, the
heteroaromatic group being substituted by at least one substituent
(e.g. one, two, three or four substituents independently) selected
from halogen (e.g. fluorine, chlorine or bromine), cyano,
C.sub.1-C.sub.4, or C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.2
haloalkyl, C.sub.1-C.sub.2 hydroxyalkyl, C.sub.1-C.sub.2 alkoxy,
C.sub.1-C.sub.2 haloalkoxy, C.sub.1-C.sub.2 alkylcarbonyl,
C.sub.1-C.sub.2 alkylcarbonyloxy, C.sub.1-C.sub.2 alkoxycarbonyl,
--NR.sup.6R.sup.7, --CONR.sup.8R.sup.9, C.sub.3-C.sub.6 or
C.sub.3-C.sub.5 or C.sub.5-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 or
C.sub.3-C.sub.5 or C.sub.5-C.sub.6 cycloalkyloxy or C.sub.3-C.sub.6
or C.sub.3-C.sub.5 or C.sub.5-C.sub.6 cycloalkylmethyl.
[0038] In another embodiment of the invention, R.sup.1 represents a
6- to 7-, 8- or 9-membered heteroaromatic group containing one or
two ring heteroatoms selected from nitrogen atoms (such as
pyridinyl, benzodiazolyl or indolyl), the heteroaromatic group
being substituted by one or two substituents independently selected
from halogen (e.g. fluorine, chlorine or bromine, particularly
chlorine), C.sub.1-C.sub.3 alkyl (e.g. methyl, ethyl or isopropyl)
and C.sub.1-C.sub.2 haloalkyl (e.g. trifluoromethyl).
[0039] In a preferred embodiment, R.sup.1 represents any one of the
following moieties or is selected from a group containing two or
more of such moieties in any combination: [0040] (i)
methyl-1,3-benzodiazolyl (e.g. 1-(methyl)-1,3-benzodiazol-2-yl),
[0041] (ii) isopropyl-1,3-benzodiazolyl (e.g.
1-(isopropyl)-1,3-benzodiazol-2-yl), [0042] (iii) methyl-indolyl
(e.g. 1-(methyl)-indol-2-yl), [0043] (iv) ethyl-indolyl (e.g.
1-(ethyl)-indol-2-yl), [0044] (v) isopropyl-indolyl (e.g.
1-(isopropyl)-indol-2-yl), [0045] (vi) di-alkyl substituted indolyl
(e.g. (1-ethyl-5-methyl)-indol-2-yl or
(1-ethyl-3-methyl)-indol-2-yl), [0046] (vii)
(1-ethyl-5-chloro)-indol-2-yl, [0047] (viii)
(3-methyl-5-chloro)-pyridin-2-yl, and [0048] (ix)
(3-trifluoromethyl-5-chloro)-pyridin-2-yl.
[0049] In one embodiment of the invention, R.sup.2 represents a
hydrogen atom, R.sup.3 represents a hydrogen atom and R.sup.4
represents a hydrogen atom.
[0050] In another embodiment, R.sup.2 represents a fluorine atom,
R.sup.3 represents a hydrogen atom and
[0051] R.sup.4 represents a hydrogen atom.
[0052] In yet another embodiment, R.sup.2 represents a hydroxyl
group, R.sup.3 represents a hydrogen atom and R.sup.4 represents a
hydrogen atom.
[0053] In a further embodiment, R.sup.2 represents a
C.sub.1-C.sub.3 alkoxy (particularly methoxy) group, R.sup.3
represents a hydrogen atom and R.sup.4 represents a hydrogen
atom.
[0054] Alternatively, when R.sup.4 represents a hydrogen atom,
R.sup.2 may together with R.sup.3 form a carbon-carbon single bond,
thereby resulting in the formation of a double bond between is the
carbon atoms to which R.sup.2 and R.sup.3 are attached, as
illustrated below:
##STR00004##
[0055] Similarly, when R.sup.3 represents a hydrogen atom, R.sup.2
may together with R.sup.4 form a carbon-carbon single bond, thereby
resulting in the formation of a double bond between the carbon
atoms to which R.sup.2 and R.sup.4 are attached, as illustrated
below:
##STR00005##
[0056] R.sup.5 represents a 5- to 6-membered heteroaromatic group
containing from one to three ring heteroatoms selected from
nitrogen atoms, the heteroaromatic group being substituted by at
least one substituent (e.g. one, two, three or four substituents
independently) selected from halogen (e.g. fluorine, chlorine or
bromine), cyano, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 alkyl, C.sub.2-C.sub.6 or C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.6 or C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 hydroxyalkyl, C.sub.1-C.sub.6,
or C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkoxy, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 haloalkoxy, C.sub.1-C.sub.6, or
C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkylcarbonyl, C.sub.1-C.sub.6,
or C.sub.1-C.sub.4, or C.sub.1-C.sub.2 alkylcarbonyloxy,
C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or C.sub.1-C.sub.2
alkoxycarbonyl, --NR.sup.10R.sup.11, --CONR.sup.12R.sup.13,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkyloxy or
C.sub.3-C.sub.6 cycloalkylmethyl.
[0057] Examples of 5- to 6-membered heteroaromatic groups include
pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl,
pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Preferred groups
include pyridinyl, pyridazinyl and pyrazolyl, especially
4-pyridinyl, 4-pyridazinyl, 5-pyridazinyl and 4-pyrazolyl.
[0058] In one embodiment, R.sup.5 represents a 5- and/or 6-membered
heteroaromatic group containing one, two or three ring heteroatoms
selected from nitrogen atoms, the heteroaromatic group being
substituted by at least one substituent (e.g. one, two, three or
four substituents independently) selected from halogen (e.g.
fluorine, chlorine or bromine), cyano, C.sub.1-C.sub.4, or
C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2
haloalkyl, C.sub.1-C.sub.2 hydroxyalkyl, C.sub.1-C.sub.4, or
C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkoxy, C.sub.1-C.sub.2
haloalkoxy, C.sub.1-C.sub.2 alkylcarbonyl, C.sub.1-C.sub.2
alkylcarbonyloxy, C.sub.1-C.sub.2 alkoxycarbonyl,
--NR.sup.10R.sup.11, --CONR.sup.12R.sup.13, C.sub.3-C.sub.6 or
C.sub.3-C.sub.5 or C.sub.5-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 or
C.sub.3-C.sub.5 or C.sub.5-C.sub.6 cycloalkyloxy or C.sub.3-C.sub.6
or C.sub.3-C.sub.5 or C.sub.5-C.sub.6 cycloalkylmethyl.
[0059] In a further embodiment, R.sup.5 represents a 5- and/or
6-membered heteroaromatic group containing one, two or three ring
heteroatoms selected from nitrogen atoms, the heteroaromatic group
being substituted by at least one substituent (e.g. one, two, three
or four substituents independently) selected from halogen (e.g.
fluorine, chlorine or bromine), C.sub.1-C.sub.4, or
C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkyl, or
--NR.sup.10R.sup.11.
[0060] In a still further embodiment, R.sup.5 represents a 5-
and/or 6-membered heteroaromatic group containing one or two ring
heteroatoms selected from nitrogen atoms such as pyridinyl
(particularly 4-pyridinyl), pyridazinyl (particularly 4-pyridazinyl
or 5-pyridazinyl) or pyrazolyl (particularly 4-pyrazolyl), the
heteroaromatic group being substituted by one or two substituents
independently selected from halogen (particularly chlorine),
C.sub.1-C.sub.2 alkyl, and --NR.sup.10R.sup.11.
[0061] In a preferred embodiment, R.sup.5 represents any one of the
following moieties or is selected from a group containing two or
more of such moieties in any combination: [0062] (i)
2-(methylamino)-pyridin-4-yl, [0063] (ii)
2-(dimethylamino)-pyridin-4-yl, [0064] (iii)
6-chloro-pyridazin-4-yl, [0065] (iv)
3-(methylamino)-pyridazin-5-yl, [0066] (v)
3-(dimethylamino)pyridazin-5-yl, [0067] (vi)
1-(ethyl)-pyrazol-4-yl, and [0068] (vii)
(1-methyl-3-amino)-pyrazol-4-yl.
[0069] R.sup.6 and R.sup.7 each independently represent a hydrogen
atom or a C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or C.sub.1-C.sub.2
alkyl or C.sub.3-C.sub.6 or C.sub.3-C.sub.5 or C.sub.5-C.sub.6
cycloalkyl group, or R.sup.6 and R.sup.7may together with the
nitrogen atom to which they are attached form a 4-, 5-, 6- or
7-membered saturated heterocyclic ring optionally substituted by at
least one substituent (e.g. one or two substituents independently)
selected from fluorine, hydroxyl and C.sub.1-C.sub.3 alkoxy.
[0070] In one aspect, the saturated heterocyclic ring may contain a
single ring heteroatom (being the nitrogen atom to which R.sup.6
and R.sup.7 are attached). In an alternative aspect, the saturated
heterocyclic ring may contain a second ring heteroatom selected
from a nitrogen or oxygen atom.
[0071] In a first embodiment, R.sup.6 and R.sup.7 each
independently represent a hydrogen atom or a C.sub.1-C.sub.4, or
C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkyl or C.sub.3-C.sub.6,
particularly cyclopropyl, group, or R.sup.6 and R.sup.7may together
with the nitrogen atom to which they are attached form a 4- or
5-membered saturated heterocyclic ring (azetidinyl or pyrrolidinyl)
optionally substituted by one or two substituents independently
selected from fluorine, hydroxyl and C.sub.1-C.sub.3 alkoxy.
[0072] In a second embodiment, R.sup.6 and R.sup.7 each represent a
hydrogen atom.
[0073] In a third embodiment, R.sup.6 and R.sup.7 each represent a
C.sub.1-C.sub.3 alkyl group.
[0074] In a fourth embodiment, one of R.sup.6 and R.sup.7
represents a hydrogen atom and the other of R.sup.6 and R.sup.7
represents a C.sub.1-C.sub.3 alkyl group.
[0075] In a fifth embodiment, one of R.sup.6 and R.sup.7 represents
a cyclopropyl group and the other of R.sup.6 .sub.and R.sup.7
represents a C.sub.1-C.sub.3 alkyl group.
[0076] In a sixth embodiment, R.sup.6 and R.sup.7 together with the
nitrogen atom to which they are attached form an azetidinyl or
pyrrolidinyl ring optionally substituted by one or two substituents
independently selected from fluorine and hydroxyl.
[0077] In a seventh embodiment, R.sup.6 and R.sup.7 together with
the nitrogen atom to which they are attached form an unsubstituted
azetidinyl or pyrrolidinyl ring.
[0078] R.sup.8 .sub.and R.sup.9 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 alkyl group, or R.sup.8 and R.sup.9may together
with the nitrogen atom to which they are attached form a 4- to
7-membered saturated heterocyclic ring.
[0079] In an embodiment of the invention, R.sup.8 and R.sup.9 each
independently represent a hydrogen atom or a methyl group.
[0080] R.sup.10 .sub.and R.sup.11 each independently represent a
hydrogen atom or a hydroxyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4,
or C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 alkoxy or C.sub.3-C.sub.6 or C.sub.3-C.sub.5 or
C.sub.5-C.sub.6 cycloalkyl group, or R.sup.10 and R.sup.11 may
together with the nitrogen atom to which they are attached form a
4-, 5-, 6- or 7-membered saturated heterocyclic ring optionally
substituted by at least one substituent (e.g. one or two
substituents independently) selected from fluorine, hydroxyl and
C.sub.1-C.sub.3 alkoxy.
[0081] In one aspect, the saturated heterocyclic ring may contain a
single ring heteroatom (being the nitrogen atom to which R.sup.10
and R.sup.11 are attached). In an alternative aspect, the saturated
heterocyclic ring may contain a second ring heteroatom selected
from a nitrogen or oxygen atom.
[0082] In a first embodiment, R.sup.10 and R.sup.11 each
independently represent a hydrogen atom or a hydroxyl,
C.sub.1-C.sub.4, or C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkyl,
C.sub.1-C.sub.4, or C.sub.1-C.sub.3, or C.sub.1-C.sub.2 haloalkyl,
C.sub.1-C.sub.4, or C.sub.1-C.sub.3, or C.sub.1-C.sub.2 alkoxy or
C.sub.3-C.sub.6, particularly cyclopropyl, group, or R.sup.10 and
R.sup.11 may together with the nitrogen atom to which they are
attached form a 4- or 5-membered saturated heterocyclic ring
(azetidinyl or pyrrolidinyl) optionally substituted by one or two
substituents independently selected from fluorine, hydroxyl and
C.sub.1-C.sub.3 alkoxy.
[0083] In a second embodiment, R.sup.10 and R.sup.11 each represent
a hydrogen atom.
[0084] In a third embodiment, R.sup.10 and R.sup.11 each represent
a C.sub.1-C.sub.3 alkyl group.
[0085] In a fourth embodiment, one of R.sup.10 and R.sup.11
represents a hydrogen atom and the other of R.sup.10 .sub.and
R.sup.11 represents a C.sub.1-C.sub.3 alkyl group.
[0086] In a fifth embodiment, one of R.sup.10 and R.sup.11
represents a cyclopropyl group and the other of R.sup.10 and
R.sup.11 represents a C.sub.1-C.sub.3 alkyl group.
[0087] In a sixth embodiment, R.sup.10 and R.sup.11 together with
the nitrogen atom to which they are attached form an azetidinyl or
pyrrolidinyl ring optionally substituted by one or two substituents
independently selected from fluorine and hydroxyl.
[0088] In a seventh embodiment, R.sup.10 and R.sup.11 together with
the nitrogen atom to which they are attached form an unsubstituted
azetidinyl or pyrrolidinyl ring.
[0089] In an eighth embodiment, one of R.sup.10 and R.sup.11
represents a hydrogen atom or a methyl group and the other of
R.sup.10 and R.sup.11 represents a hydroxyl, methoxy or
C.sub.1-C.sub.2 haloalkyl group.
[0090] R.sup.12 and R.sup.13 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6, or C.sub.1-C.sub.4, or
C.sub.1-C.sub.2 alkyl group, or R.sup.12 and R.sup.13 may together
with the nitrogen atom to which they are attached form a 4- to
7-membered saturated heterocyclic ring.
[0091] In an embodiment of the invention, R.sup.12 and R.sup.13
each independently represent a hydrogen atom or a methyl group.
[0092] Subject to the above provisos, preferred compounds of
formula (I) are those in which: [0093] R.sup.1 represents a 6- to
9-membered heteroaromatic group containing one or two ring
heteroatoms selected from nitrogen atoms, the heteroaromatic group
being substituted by one or two substituents independently selected
from halogen, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.2 haloalkyl;
[0094] R.sup.2 represents a hydrogen or fluorine atom or a methoxy
group; [0095] R.sup.3 represents a hydrogen atom; [0096] R.sup.4
represents a hydrogen atom; [0097] R.sup.5 represents a 5- to
6-membered heteroaromatic group containing one or two ring
heteroatoms selected from nitrogen atoms, the heteroaromatic group
being substituted by one or two substituents independently selected
from halogen, C.sub.1-C.sub.2 alkyl and --NR.sup.10R.sup.11; and
[0098] R.sup.10 and R.sup.11 each independently represent a
hydrogen atom or a C.sub.1-C.sub.6 alkyl group.
[0099] Examples of preferred compounds of formula (I) according to
the invention include: [0100]
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-ca-
rbonyl}pyridin-2-amine, [0101]
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-c-
arbonyl}pyridin-2-amine (Enantiomer 1 substantially as hereinbefore
described and with reference to Example 2), [0102]
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-c-
arbonyl}pyridin-2-amine (Enantiomer 2 substantially as hereinbefore
described and with reference to Example 3), [0103]
N,N-Dimethyl-4-[3-(1-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl-
]pyridin-2-amine, [0104]
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,-
3-benzodiazole, [0105]
N-Methyl-5-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbo-
nyl}pyridazin-3-amine, [0106]
2-[1-(1-Ethyl-1H-pyrazole-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1-
,3-benzodiazole, [0107]
N,N-Dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine, [0108]
N-Methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine, [0109]
4-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridin-2--
amine, [0110]
5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin--
3-amine, [0111]
5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-am-
ine, [0112]
N,N-Dimethyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}py-
ridazin-3-amine, [0113]
N-Methyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyrida-
zin-3-amine, [0114]
2-{1-[(1-Ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-1-(propan-2-yl)-1-
H-indole, [0115]
1-Methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-carbonyl}-1H-pyra-
zol-3-amine, [0116]
1-Ethyl-2-{1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-5-methyl--
1H-indole, [0117]
5-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrid-
azin-3-amine, [0118]
5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrid-
azin-3-amine, [0119]
5-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrid-
azin-3-amine, [0120]
5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylp-
yridazin-3-amine, [0121]
5-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylp-
yridazin-3-amine, [0122]
N-Methyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine, [0123]
N,N-Dimethyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-
-3-amine, [0124]
4-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine, [0125]
4-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine, [0126]
4-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine, [0127]
5-[3-(5-Chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]-N,N-dimethylpy-
ridazin-3-amine, [0128]
4-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-car-
bonyl}-N-methylpyridin-2-amine, [0129]
5-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidin-1-yl}c-
arbonyl)-N-methylpyridazin-3-amine, [0130]
5-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-car-
bonyl}-N,N-dimethylpyridazin-3-amine, [0131]
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-
-(trifluoromethyl)pyridine, [0132]
4-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-car-
bonyl}-N,N-dimethylpyridin-2-amine, [0133]
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-me-
thylpyridin-2-amine, [0134]
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-met-
hylpyridin-2-amine, [0135]
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-me-
thylpyridazin-3-amine, [0136]
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N,N--
dimethylpyridazin-3-amine, [0137]
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-met-
hylpyridazin-3-amine, [0138]
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N,N-d-
imethylpyridazin-3-amine, [0139]
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3-
-methylpyridine, [0140]
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-fluoropiperidin-3-yl]-3--
methylpyridine, [0141]
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-me-
thyl-1H-pyrazol-3-amine, [0142]
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1-met-
hyl-1H-pyrazol-3-amine, and pharmaceutically acceptable salts of
any one thereof.
[0143] It should be noted that each of the chemical compounds
listed above represents a particular and independent aspect of the
invention.
[0144] Compounds of formula (I) and pharmaceutically acceptable
salts thereof as defined above may be prepared by a process
comprising reacting a compound of formula
##STR00006##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in
formula (I) or a salt thereof (e.g. a hydrochloride salt), with a
compound of formula
##STR00007##
wherein R.sup.5 is as defined in formula (I);
[0145] and optionally thereafter carrying out one or more of the
following procedures: [0146] removing any protecting groups [0147]
converting a compound of formula (I) into another compound of
formula (I) [0148] forming a pharmaceutically acceptable salt.
[0149] Reaction conditions for the process above will typically
require activation of the carboxylic acid of formula (III) which
can be achieved by many of the widely known `amide coupling` agents
such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or
propylphosphonic anhydride (commercially available under the trade
mark "T3P"). This can be carried out in a suitable solvent such as
dichloromethane, in the presence of a base such as triethylamine.
The compound of formula (II), or salt thereof, may be present
during activation of the carboxylic acid of formula (III), or may
be added a short while afterwards. The reactions will typically
occur at ambient room temperature (20 to 25.degree. C.). As an
alternative to carrying out the activation in situ, `pre-activated`
variants of the compound of formula (III) such as acid halides,
acid anhydrides and esters (e.g. pentafluorophenyl esters) thereof
can be used to react with the amine of formula (II) to form
compounds of formula (I) under the appropriate conditions which
will be known to the person skilled in the art.
[0150] Compounds of formula (II) in which R.sup.2 is hydrogen,
R.sup.3 is hydrogen and R.sup.4 is hydrogen may be prepared by
reacting a compound of formula (IV), R.sup.1--B(OR.sup.20).sub.2,
where R.sup.20 represents a hydrogen atom, an alkyl group, or both
groups OR.sup.20 together with the boron atom to which they are
attached form a dioxoborolane ring (such as a pinacol borane) or a
N-methyliminodiacetic acid boronate ester (MIDA boronate ester),
and R.sup.1 is as defined in formula (II), with 3-iodopyridine or
3-bromopyridine in the presence of a palladium catalyst according
to the Suzuki-Miyaura reaction (see, for example, the following
references: [0151] 1. Miyaura, Norio; Yamada, Kinji; Suzuki, Akira
(1979). "A new stereospecific cross-coupling by the
palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or
1-alkynyl halides". Tetrahedron Letters 20 (36): 3437-3440. [0152]
2. Miyaura, Norio; Suzuki, Akira (1979). "Stereoselective synthesis
of arylated (E)-alkenes by the reaction of alk-1-enylboranes with
aryl halides in the presence of palladium catalyst". Chem. Comm.
(19): 866-867. [0153] 3. Miyaura, Norio; Suzuki, Akira (1995).
"Palladium-Catalyzed Cross-Coupling Reactions of Organoboron
Compounds". Chemical Reviews 95 (7): 2457-2483. followed by a
reduction step using hydrogen gas and a platinum (IV) oxide
catalyst. In some instances removal of a protecting group, if
present, may be performed prior to the reduction step. In other
instances removal of a protecting group, if present, and alkylation
of the deprotected atom may be performed prior to the reduction
step.
[0154] Alternatively, compounds of formula (II) in which R.sup.2 is
hydrogen, R.sup.3 is hydrogen and R.sup.4 is hydrogen may be
prepared as illustrated in Scheme 1 below:
##STR00008##
[0155] In Scheme 1, `PG` denotes a nitrogen-protecting group. Step
1 is carried out in the presence of lithium
bis(trimethylsilyl)amide and
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride. The
reaction product obtained can be a mixture of enol nonaflate
isomers which, individually or taken as a mixture, is then reacted
in step 2 with a compound of formula (IV) as described above under
Suzuki-Miyaura reaction conditions. The product of step 2 is
hydrogenated in step 3 using, for example, transition metal
catalysed hydrogenation (e.g. palladium on carbon, Pd(OH).sub.2 on
carbon, or platinum (IV) oxide) and, finally, the protecting group
is removed in step 4, for example, using trifluoroacetic acid or
hydrochloric acid in dichloromethane, when PG is
tert-butoxycarbonyl (Boc) to give a compound of formula (II).
Alternatively, where PG is benzyl or 4-methoxy benzyl , the
deprotection may occur concomitantly with hydrogenation, or may
proceed stepwise, typically effected by raising either the
temperature and/or pressure of hydrogenation and/or by extending
the reaction time of hydrogenation such that hydrogenolysis of the
PG also occurs. Alternatively, where PG is benzyl or 4-methoxy
benzyl , the deprotection may be effected by treatment with
.alpha.-chloroethyl chloroformate (ACE-Cl) in a suitable solvent
such as dichloromethane or dichloroethane followed by treatment
with methanol according to the protocol of Olofson as described in
the following reference: Olofson, Martz (1984). "A New Reagent for
the Selective, High-Yield N-Dealkylation of Tertiary Amines:
Improved Syntheses of Naltrexone and Nalbuphine". J. Org. Chem. 49:
2081-2082.
[0156] Compounds of formula (II) in which R.sup.2 is other than
hydrogen may be prepared as illustrated in Scheme 2 below:
##STR00009##
[0157] In Scheme 2, `PG` denotes a nitrogen-protecting group,
R.sup.22 denotes a C.sub.1-C.sub.3 alkyl group and `R.sup.1` has
the same meaning as in formula (I). Step 1 is carried out in the
presence of an organometallic reagent (eg aryl Grignard,
R.sup.1--MgX) and then the protecting group is removed in step 2,
for example, using trifluoroacetic acid or hydrochloric acid in
dichloromethane when PG is tert-butoxycarbonyl (Boc) to give a
compound of formula (II) in which R.sup.2 represents hydroxyl.
Alternatively the product from step 1 (Intermediate A) can be
alkylated (e.g. using a C.sub.1-C.sub.3 alkyl halide and a strong
base, e.g. sodium hydride) (step 3) and the protecting group
removed in step 4 by a procedure analogous to step 2 to io give
compounds of formula (II) in which R.sup.2 represents
C.sub.1-C.sub.3 alkoxy. Intermediate A may also be treated with a
fluorinating agent (e.g. diethylaminosulfur trifluoride) (step 5)
followed by removal of the protecting group in step 6 using a
procedure analogous to step 2 to give a compound of formula (II) in
which R.sup.2 represents fluorine.
[0158] Compounds of formula (II) in which either R.sup.2 and
R.sup.3 form a carbon-carbon single bond or R.sup.2 and R.sup.4
form a carbon-carbon single bond can be prepared by treating the
product obtained from step 2 of Scheme 1 above with ACE-Cl followed
by methanol (vide supra) to remove the protecting group.
[0159] Compounds of formula (II) in which R.sup.2 and R.sup.3
together with the carbon atoms to which they are attached form a
cyclopropyl ring, or, R.sup.2 and R.sup.4 together with the carbon
atoms to which they are attached form a cyclopropyl ring may be
prepared by treating the product from step 2 of Scheme 1 with a
Simmons-Smith cyclopropanating reagent such as an organozinc
derived from diiodomethane, diethyl zinc and trifluoroacetic acid,
for example, as described in the reference by J. C. Lorenz, J.
Long, Z. Yang, S. Xue, X. Xie, Y. Shi, "A Novel Class of Tunable
Zinc Reagents (RXZnCH.sub.2Y) for Efficient Cyclopropanation of
Olefins", J. Org. Chem., 2004, 69, 327-334. The reaction may be
followed by a deprotection step to remove any protecting groups,
e.g. using ACE-Cl, or transition metal (e.g. platinum (IV) oxide)
catalytic hydrogenolysis, to give the compound of formula (II).
[0160] Certain intermediates of formula (II) are novel compounds.
Accordingly, the present invention also provides novel intermediate
compounds of formula (II), such as compounds of formula (II) in
which R.sup.1 represents a pyridinyl group substituted by one or
two substituents independently selected from halogen (e.g.
fluorine, chlorine or bromine, particularly chlorine),
C.sub.1-C.sub.3 alkyl (e.g. methyl, ethyl or isopropyl) and
C.sub.1-C.sub.2 haloalkyl (e.g. trifluoromethyl).
[0161] Compounds of formulae (III) and (IV) are either commercially
available, are well known in the literature or may be prepared
using known techniques.
[0162] It will be appreciated by those skilled in the art that in
the above processes certain functional groups such as phenol,
hydroxyl or amino groups in the reagents may need to be protected
by protecting groups. Thus, the preparation of compounds of formula
(I) may involve, at an appropriate stage, the introduction and/or
removal of one or more protecting groups.
[0163] The protection and deprotection of functional groups is
described in Protective Groups in Organic Chemistry', edited by J.
W. F. McOmie, Plenum Press (1973) and `Protective Groups in Organic
Synthesis`, 3.sup.rd edition, T. W. Greene and P. G. M. Wuts,
Wiley-Interscience (1999).
[0164] The compounds of formula (I) above may be converted to a
pharmaceutically acceptable salt thereof, preferably an acid
addition salt such as a formate, hemi-formate, hydrochloride,
hydrobromide, benzenesulphonate (besylate), saccharin (e.g.
monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate,
acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate,
succinate, valerate, propanoate, butanoate, malonate, oxalate,
1-hydroxy-2-napthoate (xinafoate), methanesulphonate or
p-toluenesulphonate salt.
[0165] In one aspect of the invention, compounds of formula (I)
defined above may bear one or more radiolabels. Such radiolabels
may be introduced by using radiolabel-containing reagents in the
synthesis of the compounds of formula (I) or may be introduced by
coupling the compounds of formula (I) to chelating moieties capable
of binding to a radioactive metal atom. Such radiolabeled versions
of the compounds may be used, for example, in diagnostic imaging
studies.
[0166] Unless stated otherwise, any atom specified herein may also
be an isotope of said atom. For example, the term "hydrogen"
encompasses .sup.1H, .sup.2H and .sup.3H. Similarly carbon atoms
are to be understood to include .sup.12C, .sup.13C and .sup.14C,
nitrogen atoms are to be understood to include 14N and, .sup.15N
and oxygen atoms are to be understood to include .sup.16O, .sup.17O
and .sup.18O.
[0167] In a further aspect of the invention, compounds of formula
(I) may be isotopically labelled. As used herein, an "isotopically
labelled" compound is one in which the abundance of a particular
nuclide at a particular atomic position within the molecule is
increased above the level at which it occurs in nature.
[0168] Compounds of formula (I) and their salts may be in the form
of hydrates or solvates which form an aspect of the present
invention. Such solvates may be formed with common organic
solvents, including but not limited to, alcoholic solvents e.g.
methanol, ethanol or isopropanol.
[0169] Where compounds of formula (I) above are capable of existing
in stereoisomeric forms, it will be understood that the invention
encompasses the use of all geometric and optical isomers (including
atropisomers) of the compounds of formula (I) and mixtures thereof
including racemates. The use of tautomers and mixtures thereof also
forms an aspect of the present invention. Enantiomerically pure
forms are particularly desired.
[0170] Compounds of formula (I) and their salts may be amorphous or
in a polymorphic form or a mixture of any of these, each of which
forms an aspect of the present invention.
[0171] The compounds of formula (I) and their pharmaceutically
acceptable salts have activity as pharmaceuticals, in particular as
prokineticin receptor modulators, and thus may be used in the
treatment of schizophrenia and other psychotic disorders (e.g.,
schizophreniform disorder, schizoaffective disorder and psychosis);
dementia (including behavioural and psychological symptoms of
dementia, BPSD) and other cognitive disorders; anxiety disorders
(e.g., generalized anxiety disorder, post-traumatic stress disorder
and panic attack); mood disorders (e.g., depressive disorders,
major depressive disorders, bipolar disorders including bipolar I
and II, bipolar mania, bipolar depression); sleep disorders;
disorders usually first diagnosed in infancy, childhood, or
adolescence (e.g., attention-deficit disorder, autistic spectrum
disorders, Rett syndrome, Fragile X syndrome, Asperger syndrome and
disruptive behaviour disorders); pain (e.g. neuropathic pain
including chemotherapy induced pain, or visceral pain, or
gastrointestinal pain); inflammatory conditions such as
inflammatory bowel disease (e.g. Crohn's disease, Coeliac disease,
ileitis, ulcerative colitis, enteropathy associated with
seronegative arthropathies, microscopic or collagenous colitis,
eosinophilic gastroenteritis, or pouchitis resulting after
proctocolectomy and ileoanal anastomosis), cholecystitis,
cholangitis, Behcet's disease, pericholangitis, graft versus host
disease, sarcoidosis and chronic gastritis (e.g., autoimmune
gastritis); neurodegenerative disorders (e.g. Parkinson's or
Alzheimer's disease or multiple sclerosis); gastrointestinal
disorders (e.g. irritable bowel syndrome (IBS) and functional
dyspepsia); autoimmune disorders (e.g. rheumatoid arthritis); and
addiction (e.g. drug addiction, alcohol addiction and nicotine
addiction).
[0172] Thus, the present invention provides a compound of formula
(I) or a pharmaceutically acceptable salt thereof as hereinbefore
defined for use in therapy, in particular for the treatment of
conditions whose development or symptoms are linked to prokineticin
receptor activity.
[0173] The present invention also provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof as
hereinbefore defined for the preparation of a medicament for the
treatment of conditions whose development or symptoms are linked to
prokineticin receptor activity.
[0174] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0175] Prophylaxis is expected to be particularly relevant to the
treatment of persons who have suffered a previous episode of, or
are otherwise considered to be at increased risk of, the disorder
or condition in question. Persons at risk of developing a
particular disorder or condition generally include those having a
family history of the disorder or condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the disorder or condition or those in the
prodromal phase of a disorder.
[0176] In particular, the compounds of formula (I) and their
pharmaceutically acceptable salts as defined above may be used in
the treatment of the positive symptoms of schizophrenia,
schizophreniform disorder or schizoaffective disorder (e.g. voices
or hallucinations), cognitive disorders (such as dementia and
impaired learning), pain (such as neuropathic pain), irritable
bowel diseases, and also irritable bowel syndrome.
[0177] The invention also provides a method of treating at least
one symptom or condition associated with schizophrenia and other
psychotic disorders (e.g., schizophreniform disorder,
schizoaffective disorder and psychosis); dementia (including
behavioural and psychological symptoms of dementia, BPSD) and other
cognitive disorders; anxiety disorders (e.g., generalized anxiety
disorder, post-traumatic stress disorder and panic attack); mood
disorders (e.g., depressive disorders, major depressive disorders,
bipolar disorders including bipolar I and II, bipolar mania,
bipolar depression); sleep disorders; disorders usually first
diagnosed in infancy, childhood, or adolescence (e.g.,
attention-deficit disorder, autistic spectrum disorders, Rett
syndrome, Fragile X syndrome, Asperger syndrome and disruptive
behaviour disorders); pain (e.g. neuropathic pain including
chemotherapy induced pain, or visceral pain, or gastrointestinal
pain); inflammatory conditions such as inflammatory bowel disease
(e.g. Crohn's disease, Coeliac disease, ileitis, ulcerative
colitis, enteropathy associated with seronegative arthropathies,
microscopic or collagenous colitis, eosinophilic gastroenteritis,
or pouchitis resulting after proctocolectomy and ileoanal
anastomosis), cholecystitis, cholangitis, Behcet's disease,
pericholangitis, graft versus host disease, sarcoidosis and chronic
gastritis (e.g., autoimmune gastritis); neurodegenerative disorders
(e.g. Parkinson's or Alzheimer's disease or multiple sclerosis);
gastrointestinal disorders (e.g. irritable bowel syndrome (IBS) and
functional dyspepsia); autoimmune disorders (e.g. rheumatoid
arthritis); and addiction (e.g. drug addiction, alcohol addiction
and nicotine addiction) which comprises administering to a patient
in need thereof a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof as
hereinbefore defined.
[0178] Such symptoms and conditions include, but are not limited
to, anxiety, agitation, hostility, panic, an eating disorder, an
affective symptom, a mood symptom, a negative and positive
psychotic symptom commonly associated with psychosis and
neurodegenerative disorder.
[0179] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary with the compound employed, the
mode of administration, the treatment desired and the disorder
indicated. For example, the daily dosage of a compound according to
the invention (i.e. a compound of formula (I) or a pharmaceutically
acceptable salt thereof), if inhaled, may be in the range from 0.05
micrograms per kilogram body weight (m/kg) to 100 micrograms per
kilogram body weight (.mu.g/kg). Alternatively, if the compound is
administered orally, then the daily dosage of the compound of the
invention may be in the range from 0.01 micrograms per kilogram
body weight (m/kg) to 100 milligrams per kilogram body weight
(mg/kg).
[0180] The compounds of formula (I) and pharmaceutically acceptable
salts thereof may be used on their own but will generally be
administered in the form of a pharmaceutical composition in which
the formula (I) compound/salt (active ingredient) is in association
with a pharmaceutically acceptable adjuvant, diluent or
carrier.
[0181] Therefore the present invention further provides a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt thereof as hereinbefore defined,
in association with a pharmaceutically acceptable adjuvant, diluent
or carrier.
[0182] The invention still further provides a process for the
preparation of a pharmaceutical composition of the invention which
comprises mixing a compound of formula (I) or a pharmaceutically
acceptable salt thereof as hereinbefore defined with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0183] Conventional procedures for the selection and preparation of
suitable pharmaceutical formulations are described in, for example,
"Pharmaceutics--The Science of Dosage Form Design", M. E. Aulton,
Churchill Livingstone, 1988.
[0184] Pharmaceutically acceptable adjuvants, diluents or carriers
that may be used in the pharmaceutical compositions of the
invention are those conventionally employed in the field of
pharmaceutical formulation, and include, but are not limited to,
sugars, sugar alcohols, starches, ion exchangers, alumina,
aluminium stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycerine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulphate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0185] The pharmaceutical compositions of the present invention may
be administered orally, parenterally, by inhalation spray,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. Oral administration is preferred. The pharmaceutical
compositions of the invention may contain any conventional
non-toxic pharmaceutically acceptable adjuvants, diluents or
carriers. The term parenteral as used herein includes subcutaneous,
intracutaneous, intravenous, intramuscular, intra-articular,
intrasynovial, intrasternal, intrathecal, intralesional and
intracranial injection or infusion techniques.
[0186] The pharmaceutical compositions may be in the form of a
sterile injectable preparation, for example, as a sterile
injectable aqueous or oleaginous suspension. The suspension may be
formulated according to techniques known in the art using suitable
dispersing or wetting agents (such as, for example, Tween 80) and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable diluents and
solvents that may be employed are mannitol, water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed including synthetic mono- or diglycerides. Fatty acids,
such as oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural pharmaceutically
acceptable oils, such as olive oil or castor oil, especially in
their polyoxyethylated versions. These oil solutions or suspensions
may also contain a long-chain alcohol diluent or dispersant.
[0187] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, powders, granules, and
aqueous suspensions and solutions. These dosage forms are prepared
according to techniques well-known in the art of pharmaceutical
formulation. In the case of tablets for oral use, carriers which
are commonly used include lactose and corn starch. Lubricating
agents, such as magnesium stearate, are also typically added. For
oral administration in a capsule form, useful diluents include
lactose and dried corn starch. When aqueous suspensions are
administered orally, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening
and/or flavouring and/or colouring agents may be added.
[0188] The pharmaceutical compositions of the invention may also be
administered in the form of suppositories for rectal
administration. These compositions can be prepared by mixing the
active ingredient with a suitable non-irritating excipient which is
solid at room temperature but liquid at the rectal temperature and
therefore will melt in the rectum to release the active ingredient.
Such materials include, but are not limited to, cocoa butter,
beeswax and polyethylene glycols.
[0189] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilising or dispersing agents known in the
art.
[0190] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% w (per cent
by weight), more preferably from 0.05 to 80% w, still more
preferably from 0.10 to 70% w, and even more preferably from 0.10
to 50% w, of active ingredient, all percentages by weight being
based on total composition.
[0191] The compounds of formula (I) and pharmaceutically acceptable
salts thereof as defined above may also be administered in
conjunction with other compounds used for the treatment of the
above conditions.
[0192] The invention therefore further relates to combination
therapies wherein a compound of formula (I) or a pharmaceutically
acceptable salt thereof as previously defined or a pharmaceutical
composition or formulation comprising a compound of formula (I) or
a pharmaceutically acceptable salt thereof as previously defined is
administered with another therapeutic agent or agents, for the
treatment of one or more of the conditions previously indicated.
Such therapeutic agents may be selected from the following:
[0193] (i) antidepressants such as, for example, amitriptyline,
amoxapine, bupropion, citalopram, clomipramine, desipramine,
doxepin duloxetine, elzasonan, escitalopram, fluvoxamine,
fluoxetine, gepirone, imipramine, ipsapirone, maprotiline,
nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline,
reboxetine, robaizotan, sertraline, sibutramine, thionisoxetine,
tranylcypromaine, trazodone, trimipramine, venlafaxine, and
equivalents and pharmaceutically active isomer(s) and/or
metabolite(s) thereof;
[0194] (ii) atypical antipsychotics including, for example,
quetiapine and pharmaceutically active isomer(s) and/or
metabolite(s) thereof;
[0195] (iii) antipsychotics including, for example, amisulpride,
aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine,
clozapine, chlorpromazine, debenzapine, divalproex, duloxetine,
eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine,
mesoridazine, olanzapine, paliperidone, perlapine, perphenazine,
phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine,
risperidone, sertindole, sulpiride, suproclone, suriclone,
thioridazine, trifluoperazine, trimetozine, valproate, valproic
acid, zopiclone, zotepine, ziprasidone, and equivalents and
pharmaceutically active isomer(s) and/or metabolite(s) thereof;
[0196] (iv) anxiolytics including, for example, alnespirone,
azapirones, benzodiazepines, barbiturates, and equivalents and
pharmaceutically active isomer(s) and/or metabolite(s) thereof.
Example anxiolytics include adinazolam, alprazolam, balezepam,
bentazepam, bromazepam, brotizolam, buspirone, clonazepam,
clorazepate, chlordiazepoxide, cyprazepam, diazepam,
diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam,
fosazepam, lorazepam, lormetazepam, meprobamate, midazolam,
nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate,
trepipam, temazepam, triazolam, uldazepam, and zolazepam; and
equivalents and pharmaceutically active isomer(s) and/or
metabolite(s) thereof;
[0197] (v) anticonvulsants including, for example, carbamazepine,
valproate, lamotrigine, and gabapentin, and equivalents and
pharmaceutically active isomer(s) and/or metabolite(s) thereof;
[0198] (vi) Alzheimer's therapies including, for example,
donepezil, memantine, tacrine, and equivalents and pharmaceutically
active isomer(s) and/or metabolite(s) thereof;
[0199] (vii) Parkinson's therapies including, for example,
deprenyl, L-dopa, Requip, Mirapex, monoamine oxidase type B (MAO-B)
inhibitors such as selegiline and rasagiline, catechol-O-methyl
transferase (COMT) inhibitors such as Tasmar, A-2 inhibitors,
dopamine re-uptake inhibitors, NMDA antagonists, Nicotine agonists,
and Dopamine agonists and inhibitors of neuronal nitric oxide
synthase, and equivalents and pharmaceutically active isomer(s)
and/or metabolite(s) thereof;
[0200] (viii) migraine therapies including, for example,
almotriptan, amantadine, bromocriptine, butalbital, cabergoline,
dichloralphenazone, eletriptan, frovatriptan, lisuride,
naratriptan, pergolide, pramipexole, rizatriptan, ropinirole,
sumatriptan, zolmitriptan, and zomitriptan, and equivalents and
pharmaceutically active isomer(s) and/or metabolite(s) thereof;
[0201] (ix) stroke therapies including, for example, abciximab,
activase, NXY-059, citicoline, crobenetine, desmoteplase,
repinotan, traxoprodil, and equivalents and pharmaceutically active
isomer(s) and/or metabolite(s) thereof;
[0202] (x) urinary incontinence therapies including, for example,
darafenacin, falvoxate, oxybutynin, propiverine, robalzotan,
solifenacin, and tolterodine, and equivalents and pharmaceutically
active isomer(s) and/or metabolite(s) thereof;
[0203] (xi) neuropathic pain therapies including, for example,
gabapentin, lidoderm, and pregablin, and equivalents and
pharmaceutically active isomer(s) and/or metabolite(s) thereof;
[0204] (xii) nociceptive pain therapies such as, for example,
celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib,
diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents
and pharmaceutically active isomer(s) and/or metabolite(s)
thereof;
[0205] (xiii) insomnia therapies including, for example,
allobarbital, alonimid, amobarbital, benzoctamine, butabarbital,
capuride, chloral, cloperidone, clorethate, dexclamol,
ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine,
mecloqualone, melatonin, mephobarbital, methaqualone, midaflur,
nisobamate, pentobarbital, phenobarbital, propofol, roletamide,
triclofos, secobarbital, zaleplon, and Zolpidem, and equivalents
and pharmaceutically active isomer(s) and/or metabolite(s)
thereof;
[0206] (xiv) mood stabilizers including, for example,
carbamazepine, divalproex, gabapentin, lamotrigine, lithium,
olanzapine, quetiapine, valproate, valproic acid, and verapamil,
and equivalents and pharmaceutically active isomer(s) and/or
metabolite(s) thereof;
[0207] (xv) 5HT1B ligands such as, for example, compounds disclosed
in WO 99/05134 and WO 02/08212;
[0208] (xvi) mGluR2 agonists;
[0209] (xvii) alpha 7 nicotinic agonists such as, for example,
compounds disclosed in WO 96/006098, WO 97/030998, WO 99/003859, WO
00/042044, WO 01/029034, WO 01/60821, WO 01/36417, WO 02/096912, WO
03/087102, WO 03/087103, WO 03/087104, WO 2004/016617, WO
2004/016616, and WO 2004/019947;
[0210] (xviii) chemokine receptor CCR1 inhibitors; and
[0211] (xix) delta opioid agonists such as, for example, compounds
disclosed in WO 97/23466 and WO 02/094794.
[0212] Such combination products employ the compound of formula (I)
or a pharmaceutically acceptable salt thereof as previously defined
within the dosage range described herein and the other
pharmaceutically active agent within approved dosage ranges and/or
the dosage such as described in the publication reference.
[0213] In a further aspect the present invention provides a
combination (for example for the treatment of schizophrenia,
cognitive disorders or pain) of a compound of formula (I) or a
pharmaceutically acceptable salt thereof as hereinbefore defined
and one or more agents independently selected from carbamazepine,
olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine,
risperidone, aripiprazole, ziprasidone and lithium.
[0214] The invention also provides a pharmaceutical product
comprising, in combination, a preparation of a first active
ingredient which is a compound of formula (I) or a pharmaceutically
acceptable salt thereof as hereinbefore defined, and a preparation
of a second active ingredient which is carbamazepine, olanzapine,
quetiapine, verapamil, lamotrigine, oxcarbazepine, risperidone,
aripiprazole, ziprasidone or lithium, for simultaneous, sequential
or separate use in therapy.
[0215] In another aspect, the invention provides a kit comprising a
preparation of a first active ingredient which is a compound of
formula (I) or a pharmaceutically acceptable salt thereof as
hereinbefore defined, and a preparation of a second active
ingredient which is carbamazepine, olanzapine, quetiapine,
verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazole,
ziprasidone or lithium, and instructions for the simultaneous,
sequential or separate administration of the preparations to a
patient in need thereof.
[0216] The present invention will now be further explained by
reference to the following illustrative examples, in which the
starting materials and reagents used are available from commercial
suppliers.
[0217] is Nuclear magnetic resonance (NMR) spectra were recorded at
400 MHz and at 300.3K unless otherwise stated; the chemical shifts
(.delta.) are reported in parts per million. Spectra were recorded
using either a Bruker 400 Avance instrument fitted with a 5 mm BBFO
probe or DUL probe with instrument controlled by Bruker TopSpin 2.1
software, or by a Jeol Lambda spectrometer (JN-LMA400) instrument
fitted with a 5 mm Jeol TH5 probe with instrument controlled by
Jeol Delta software v4.3.5.
[0218] In respect of NMR analysis, compounds of the formula (I)
frequently exhibit signal splitting and/or broadening due to
conformationally restricted motion of the pendant substituents of
the N-acyl piperidine ring. These effects are temperature and
solvent dependent and can complicate the assignment of signals and
coupling constants. For the avoidance of doubt, such split or
broadened signals have been assigned a chemical shift range as
observed and have been designated as multiplets.
[0219] Purity was assessed using one or more of the following:
[0220] UPLC with UV (photodiode array) detection over a wide range
of wavelengths, normally 220-450 nm, using a Waters Acquity UPLC
system equipped with Acquity UPLC BEH or HSS C18 columns (2.1 mm
id.times.50 mm long) operated at 50 or 60.degree. C. Mobile phases
typically consisted of acetonitrile or methanol mixed with water
containing either 0.05% formic acid or 0.025% ammonia. Mass spectra
were recorded with a Waters SQD single quadrupole mass spectrometer
using atmospheric pressure ionisation. [0221] Perkin Elmer 200
series system equipped with Agilent Poroshell 120 column
(SB-C.sub.18, 4.6 mm id.times.30 mm, 2.7 m) operated at 20.degree.
C. Mobile phases consisted of acetonitrile and water, both
containing 0.1% v/v formic acid. Mass spectra were recorded with a
PE SCIEX API 2000 MS/MS mass spectrometer. The system was
controlled by Analyst software (version 1.5.1).
[0222] Compounds were purified using normal phase chromatography on
silica, using Biotage or Isolute KP-Sil cartridges or Kinesis Telos
Silica cartridges, or on basic silica, using Biotage or Isolute
KP-NH cartridges, or by reverse phase chromatographic methods,
using Biotage or Isolute KP-C18-HS cartridges or by SCX-2
catch-release cartridges, or by Preparative HPLC, or by
Supercritical Fluid Chromatography (SFC).
[0223] Preparative HPLC was performed using one or more of the
following: [0224] Agilent Technologies 1100 Series system or a
Waters autopurification LC/MS system typically using Waters 19 mm
id.times.100 mm long C18 columns such as XBridge or SunFire 5 .mu.m
materials at room temperature. [0225] Gilson HPLC system using
Waters XBridge Column (C18, 5 .mu.m, 19 mm id.times.250 mm),
controlled by UniPoint software (version 2.10) [0226] Waters
autopurification LC/MS system using Varian Column (C18, 5 .mu.m,
21.2 mm id.times.150 mm), controlled by MassLynx software (version
4.0 SP4) Mobile phases typically consisted of acetonitrile or
methanol mixed with water containing either 0.1% formic acid or
0.1% ammonia, unless stated otherwise.
[0227] Room temperature in the following examples means the
temperature ranging from 20.degree. C. to 25.degree. C.
[0228] The following abbreviations are used in the Examples: [0229]
ACE-Cl .alpha.-chloroethyl chloroformate [0230] ACN acetonitrile
[0231] aq. aqueous [0232] CHCl.sub.3 chloroform [0233] CV column
volumes [0234] DCM dichloromethane [0235] DMAP
4-(dimethylamino)pyridine [0236] DMSO dimethyl sulfoxide [0237] DMF
dimethylformamide [0238] DPPF 1,1'-bis(diphenylphosphanyl)
ferrocene [0239] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
[0240] EtOAc ethyl acetate [0241] EtOH ethanol [0242] g grams
[0243] HBr hydrobromic acid [0244] HCl hydrochloric acid [0245]
HOAt 1-hydroxy-7-azabenzotriazole [0246] HPLC high pressure liquid
chromatography [0247] LCMS liquid chromatographic mass spectrometry
[0248] LiHMDS lithium bis(trimethylsilyl)amide [0249] MgSO.sub.4
magnesium sulphate [0250] MeOH methanol [0251] mg milligrams [0252]
mins minutes [0253] mL millilitres [0254] mmol millimoles [0255] MS
mass spectrometry [0256] NaHCO.sub.3 sodium hydrogen carbonate
[0257] NaOH sodium hydroxide [0258] Na.sub.2SO.sub.4 sodium
sulphate [0259] NH.sub.3 ammonia [0260] NH.sub.4Cl ammonium
chloride [0261] NMP 1-methyl-2-pyrrolidone [0262] NMR nuclear
magnetic resonance [0263] ppm parts per milion [0264] Rt retention
time [0265] sat. saturated [0266] SFC supercritical fluid
chromatography [0267] TFA trifluoroacetic acid [0268] THF
tetrahydrofuran
1. INTERMEDIATES
Intermediate 1 6-Chloropyridazine-4-carboxylic acid
##STR00010##
[0270] To a stirred solution of methyl
6-chloropyridazine-4-carboxylate (CAS 1093860-48-0, 5.05 g, 29.3
mmol) in THF (10 mL)/water (20 mL) was added lithium hydroxide
(1.402 g, 58.5 mmol). After 90 minutes the reaction mixture was
acidified to pH 1-2 with conc. HCl (11.8 M, 5 mL) and concentrated
in vacuo to remove the THF. The resultant precipitate was stirred
in the predominantly aqueous medium at ambient temperature for
approximately 30 minutes and was then filtered through a sinter
under vacuum and dried in a vacuum oven afford the title
compound.
[0271] MS ES.sup.+:159
Intermediate 2 1-Methyl-2-(piperidin-3-yl)-1H-indole
##STR00011##
[0273] To a stirred solution of
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole
(Intermediate 3; 0.217 g, 0.718 mmol) in ethanol (10 mL) was added
ammonium formate (0.452 g, 7.18 mmol) and palladium hydroxide on
carbon (20 wt. %, 0.050 g). The reaction mixture was heated to
reflux under an atmosphere of nitrogen for 5.5 hours. The reaction
was then removed from heat and allowed to cool and was filtered
through diatomaceous earth. The solvent was removed in vacuo and
the crude product was purified by reverse phase preparative HPLC
eluted with acetonitrile / water (with 0.1% ammonia) to afford the
title compound.
[0274] MS ES.sup.+:215
Intermediate 3
2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole
##STR00012##
[0276] A microwave vial was charged with
1-benzyl-1,2,5,6-tetrahydropyridin-3-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 4;
0.986 g, 2.093 mmol),
1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
(CAS 596819-10-2; 0.565 g, 2.197 mmol) and potassium carbonate
(0.868 g, 6.28 mmol) in dioxane (15 mL)/water (3.75 mL). The
stirred mixture was degassed by bubbling nitrogen through it for 5
minutes. Tetrakis(triphenylphosphine)palladium(0) (0.121 g, 0.105
mmol) was added and the mixture was degassed for another minute
before being sealed and irradiated in a microwave reactor at
100.degree. C. for 20 minutes. The reaction mixture was diluted
with EtOAc and washed with water then brine and the organic part
was loaded onto a pre-equilibrated cation exchange cartridge
(SCX-2) and was eluted with EtOAc then EtOAc/[1M NH.sub.3 in MeOH]
(4:1) and then EtOAc/[2M NH.sub.3 in MeOH] (4:1). The product
containing fractions were combined and reduced in vacuo to afford
the title compound. MS ES.sup.+:303
Intermediate 4 1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
##STR00013##
[0278] 1-Benzylpiperidin-3-one hydrate hydrochloride (CAS
50606-58-1) was freshly converted to free base by dissolving in
water/ACN (1:1, 0.1 g/mL) and loading onto an SCX-2 cartridge (5 g
sorbent/1 g substrate). The cartridge was washed with
water/acetonitrile (10 vols), acetonitrile (10 vols) then the free
base eluted with acetonitrile/[2M NH.sub.3 in MeOH] (4:1) (50
vols). 1-Benzylpiperidin-3-one (6.45 g, 34.1 mmol) was dissolved in
anhydrous THF (100 mL) and the solution was stirred at -78.degree.
C. under a nitrogen atmosphere. To the stirred solution was added
LiHMDS [1.0M in THF] (47.7 ml, 47.7 mmol) over 5 minutes. To the
stirred reaction mixture was added
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (CAS
375-72-4; 9.18 ml, 51.1 mmol). After 75 minutes the reaction
mixture removed from the cold-bath and allowed to warm to ambient
temperature. After 1 hour the reaction was quenched with saturated
aqueous NaHCO.sub.3, concentrated in vacuo to approximately one
third (1/3) volume and extracted into diethyl ether. The organic
phase was back extracted with brine and dried over
Na.sub.2SO.sub.4. The crude product was purified by is column
chromatography (silica gel) eluted with 0-20% EtOAc in petroleum
ether 40-60 to give the title compound.
[0279] MS ES.sup.+:472
Intermediate 5
2-{1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
##STR00014##
[0281] To a stirred solution of
1-methyl-2-(piperidin-3-yl)-1H-indole (Intermediate 2; 0.083 g,
0.387 mmol) and 6-chloropyridazine-4-carboxylic acid (Intermediate
1; 0.074 g, 0.465 mmol) in dichloromethane (2 mL) was added
triethylamine (0.108 ml, 0.775 mmol) and then
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50
wt. % solution in EtOAc) (0.577 ml, 0.968 mmol). The reaction
mixture was stirred at ambient temperature for 20 hours. The
reaction was quenched with saturated aqueous NaHCO.sub.3 and the
mixture was separated using a phase separator cartridge. The
aqueous was extracted with more DCM and the combined organics were
eluted through a cation exchange cartridge (SCX-2, 1 g). The
solvent was removed in vacuo afford the title compound which was
used without further purification.
[0282] MS ES.sup.+:355
Intermediate 6 1-Ethyl-2-(piperidin-3-yl)-1H-indole
##STR00015##
[0284] A solution of
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-ethyl-1H-indole
(Intermediate 7; 0.27 g, 0.853 mmol) in MeOH (30 mL) was cycled
through a hydrogen generating flow reactor fitted with a 20%
palladium(II) hydroxide on carbon catalyst cartridge at ambient
temperature and pressure at 1.0 ml/min flow rate. After 5 hours
hydrogen generation was stopped and the eluent was flushed from the
reactor and the system was washed through with MeOH and
concentrated in vacuo to afford the title compound.
[0285] MS ES.sup.+:229
Intermediate 7
2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-ethyl-1H-indole
##STR00016##
[0287] To a stirred solution of
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole (Intermediate
8; 0.5 g, 1.734 mmol) in DMF (5 mL) was added sodium hydride (60
wt. % in mineral oil) (0.083 g, 2.081 mmol). After 20 minutes
iodoethane (0.209 ml, 2.60 mmol) was added. The vial was purged
with nitrogen, sealed and stirred at ambient temperature. After
16.5 hours the reaction quenched with saturated aqueous NH.sub.4Cl.
The mixture was partitioned between EtOAc and saturated aqueous
NaHCO.sub.3, the aqueous layer was removed and the organic phase
was washed with water then brine. The crude product was purified by
column chromatography (silica gel) eluted with 0-25% ethyl
acetate/petrol to afford the title compound.
[0288] MS ES.sup.+:317
Intermediate 8
2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole
##STR00017##
[0290] To a stirred solution of tert-butyl
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-1-carboxylate
(Intermediate 9; 3.44 g, 8.85 mmol) in DCM (45 mL) was added TFA (5
mL). The reaction was stirred at ambient temperature. After 18
hours the reaction mixture was concentrated in vacuo, azeotroped
with DCM and the residue was neutralised by addition of 2 M ammonia
in methanol and concentrated in vacuo. The crude product was
dissolved in DCM and loaded onto pre-equilibrated cation exchange
cartridge (SCX-2, 50 g). This was washed with DCM then eluted off
with DCM/[2M NH.sub.3 in MeOH]. The crude product was purified by
column chromatography (silica gel) eluted with 0-15% {EtOAc/[2M
NH.sub.3 in MeOH (9:1)}/petroleum ether 40-60 to afford the title
compound.
[0291] MS ES.sup.+:289
Intermediate 9 tert-Butyl
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole-1-carboxylate
##STR00018##
[0293] Prepared as described for
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole
(Intermediate 3) from 1-benzyl-1,2,5,6-tetrahydropyridin-3-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 4;
5.62 g, 11.92 mmol) and
{1-[(tert-butoxy)carbonyl]-1H-indol-2-yl}boronic acid (CAS
213318-44-6; 3.11 g, 11.92 mmol) using
tetrakis(triphenylphosphine)palladium(0) (0.689 g, 0.596 mmol) and
potassium carbonate (4.94 g, 35.8 mmol) in water (8 mL) and
1,4-dioxane (32 mL) and irradiated in a microwave at 100.degree. C.
for 20 minutes to afford the title compound.
[0294] MS ES.sup.+:389
Intermediate 10
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole
##STR00019##
[0296] Prepared as described for Intermediate 5, from
6-chloropyridazine-4-carboxylic acid (Intermediate 1; 65.8 mg,
0.415 mmol) and 1-ethyl-2-(piperidin-3-yl)-1H-indole (Intermediate
6; 79 mg, 0.346 mmol) to afford the title compound.
[0297] MS ES.sup.+:369
Intermediate 11
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-in-
dole
##STR00020##
[0299] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 6-chloropyridazine-4-carboxylic acid
(Intermediate 1; 0.076 g, 0.480 mmol) and
2-(piperidin-3-yl)-1-(propan-2-yl)-1H-indole (Intermediate 12;
0.097 g, 0.400 mmol) to afford the title compound.
[0300] MS ES.sup.+:383
Intermediate 12 2-(Piperidin-3-yl)-1-(propan-2-yl)-1H-indole
##STR00021##
[0302] Prepared as described for
1-ethyl-2-(piperidin-3-yl)-1H-indole (Intermediate 6) from
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-(propan-2-yl)-1H-indole
(Intermediate 13; 0.3 g, 0.908 mmol), except that the reaction
cycling time was 2.5 hours, to afford the title compound.
[0303] MS ES.sup.+:243
Intermediate 13
2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-(propan-2-yl)-1H-indole
##STR00022##
[0305] To a stirred solution of palladium(II) acetate (5.88 mg,
0.026 mmol) and 1,3-bis-(2,6-diisopropylphenyl)-imidazolium
chloride (0.011 g, 0.026 mmol) in toluene (1.0 mL) was added
potassium 2-methylpropan-2-olate (0.117 g, 1.047 mmol). The
reaction mixture was stirred at ambient temperature in a sealed
tube under a nitrogen atmosphere for 10 minutes after which time a
solution of
2-[2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)ethynyl]-N-(propan-2-yl)ani-
line (Intermediate 14; 0.173 g, 0.524 mmol) in toluene (1 mL) was
added. The reaction mixture was heated to 80.degree. C. for 50
minutes and then allowed to cool to ambient temperature before
being diluted with EtOAc and washed with saturated aqueous
NaHCO.sub.3 and then brine. The combined organics were dried over
MgSO.sub.4 and purified by column chromatography (silica gel)
eluted with 0-25% ethyl acetate/petroleum 40-60 to afford the title
compound.
[0306] MS ES.sup.+:331
Intermediate 14
2-[2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)ethynyl]-N-(propan-2-yl)ani-
line
##STR00023##
[0308] To a stirred solution of 2-ethynyl-N-(propan-2-yl)aniline
(Intermediate 15; 0.242 g, 1.520 mmol) and
1-benzyl-1,2,5,6-tetrahydropyridin-3-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Intermediate 4;
0.716 g, 1.520 mmol) in DMF (7.5 mL) was added triethylamine (0.636
ml, 4.56 mmol), palladium(II) acetate (0.014 g, 0.061 mmol),
copper(I) iodide (0.014 g, 0.076 mmol) and DPPF (0.051 g, 0.091
mmol). The reaction flask was purged with nitrogen and heated at
70.degree. C. under nitrogen. After 2 hours the reaction was
allowed to cool, diluted with EtOAc, washed with water then brine.
The crude product was purified by column chromatography (silica
gel) eluted with 0-25% EtOAc/petroleum ether 40-60 to afford the
title compound.
[0309] MS ES.sup.+:331
Intermediate 15 2-Ethynyl-N-(propan-2-yl)aniline
##STR00024##
[0311] To a stirred solution of 2-ethynylaniline (CAS 52670-38-9; 1
g, 8.54 mmol) in dichloromethane (25 mL) was added acetic acid
(1.955 ml, 34.1 mmol), 2-methoxyprop-1-ene (CAS 116-11-0; 3.27 ml,
34.1 mmol) and then sodium triacetoxyborohydride (2.71 g, 12.80
mmol). The reaction was stirred at ambient temperature for 20 hours
and then quenched with saturated aqueous NaHCO.sub.3. The organic
phase was separated and the aqueous was extracted with DCM. The
crude product was purified by column chromatography (silica gel)
eluted with 0-10% ethyl acetate/petroleum ether 40-60 to afford the
title compound.
[0312] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.28 (d,
J=6.32 Hz, 6H) 3.42 (s, 1H) 3.59-3.80 (m, 1H) 6.55-6.69 (m, 2H)
7.14-7.27 (m, 1H) 7.35 (dd, J=7.58, 1.52 Hz, 1H)
Intermediate 16 tert-Butyl
N-(1-methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}-1H-
-pyrazol-3-yl)carbamate
##STR00025##
[0314] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 2-(piperidin-3-yl)-1-(propan-2-yl)-1H-indole
(Intermediate 12; 0.048 g, 0.198 mmol) and
3-{[tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic
acid (Intermediate 17; 0.057 g, 0.238 mmol) in dichloromethane (1
mL), except that the work-up was performed as follows:
[0315] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and then diluted in EtOAc and washed first with
saturated aqueous NaHCO.sub.3 and then dilute aqueous HCl (3%) and
then brine. The solvent was removed in vacuo to afford the title
compound which was used without further purification.
[0316] MS ES.sup.+:466
Intermediate 17
3-{[(tert-Butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic
acid
##STR00026##
[0318] To a stirred suspension of ethyl
3-{bis[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate
(Intermediate 18; 2.18 g, 5.90 mmol) in EtOH (30 mL) was added
sodium hydroxide solution (2M, 5.90 mL, 11.80 mmol) under a
nitrogen atmosphere. The reaction was heated to reflux for 4 hours.
Additional sodium hydroxide (2M, 5.90 mL, 11.80 mmol) was added and
the reaction was heated to reflux for a further 2 hours. The
reaction mixture was concentrated in vacuo and was acidified with
aqueous hydrogen chloride (2M) then partitioned between ethyl
acetate and water. The phases were separated and the aqueous phase
extracted with ethyl acetate. The combined organics were dried
(MgSO.sub.4) and concentrated in vacuo to afford the title compound
that was used without purification.
[0319] MS ES.sup.-:240
Intermediate 18 Ethyl
3-{bis[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylate
##STR00027##
[0321] To a mixture of ethyl
3-amino-1-methyl-1H-pyrazole-4-carboxylate (CAS 21230-43-3; 1 g,
5.91 mmol), triethylamine (2.472 mL, 17.73 mmol) and DMAP (0.01 g,
0.082 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate
(3.23 g, 14.78 mmol). The reaction was heated to reflux for 48
hours. Additional di-tert-butyl dicarbonate (3.23 g, 14.78 mmol) is
was added and the solution heated to reflux overnight. The mixture
was partitioned between ethyl acetate and water. The phases were
separated and the aqueous extracted with ethyl acetate. The
combined organics were washed with brine, passed through a phase
separator cartridge to remove the aqueous phase and concentrated in
vacuo to afford the title compound, used in the next step without
further purification.
[0322] MS ES.sup.+:370
Intermediate 19 1-Ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole
hemi-formate
##STR00028##
[0324] To a solution of 1-ethyl-5-methyl-2-(pyridin-3-yl)-1H-indole
(Intermediate 20; 0.75 g, 3.17 mmol) and HCl (32%, 0.27 mL, 3.17
mmol) in EtOH (30 mL) under an atmosphere of nitrogen was added
platinum(IV) oxide (0.072 g, 0.317 mmol). The reaction vessel was
evacuated and back-filled with hydrogen gas and the reaction was
stirred at ambient temperature for 2 days during which time the
hydrogen atmosphere was replenished three times. The reaction
mixture was filtered through diatomaceous earth, concentrated in
vacuo and purified by reverse phase preparative HPLC eluted with
acetonitrile / water (with 0.1% formic acid) to afford the title
compound.
[0325] MS ES.sup.+:243
Intermediate 20 1-Ethyl-5-methyl-2-(pyridin-3-yl)-1H-indole
##STR00029##
[0327] To a stirred suspension of sodium hydride (60% in mineral
oil, 0.428 g, 10.69 mmol) in DMF (70 mL) at 0.degree. C. was added
a solution of 5-methyl-2-(pyridin-3-yl)-1H-indole (Intermediate 21;
1.485 g, 7.13 mmol) in DMF (15 mL), dropwise, over 20 minutes.
Iodoethane (2.22 g, 14.26 mmol) was added and the reaction mixture
was stirred at 0.degree. C. for 1 hour, and then allowed to warm to
ambient temperature and stirred for another 3 hours. The reaction
mixture was poured onto ice/water and extracted with DCM. The
combined organics were dried (Na.sub.2SO.sub.4) and the crude
product was purified by column chromatography (silica gel) eluted
with 12% EtOAc in petroleum ether to afford the title compound.
[0328] MS ES.sup.+:237
Intermediate 21 5-Methyl-2-(pyridin-3-yl)-1H-indole
##STR00030##
[0330] To a stirred solution of tert-butyl
5-methyl-2-(pyridin-3-yl)-1H-indole-1-carboxylate (Intermediate 22,
3.37 g, 10.93 mmol) in DCM (33.7 mL) was added anisole (16.85 mL)
and TFA (33.7 mL). The reaction mixture was stirred at ambient
temperature overnight and was then concentrated in vacuo, quenched
with saturated aqueous NaHCO.sub.3 and extracted with DCM. The
organic phase was further treated with saturated aqueous
NaHCO.sub.3, dried (Na.sub.2SO.sub.4), concentrated in vacuo and
triturated with diethyl ether to afford the title compound.
[0331] MS ES.sup.+:209
Intermediate 22 tert-Butyl
5-methyl-2-(pyridin-3-yl)-1H-indole-1-carboxylate
##STR00031##
[0333] To a stirred mixture of 3-iodopyridine (CAS 1120-90-7; 2.03
g, 9.91 mmol) and
{1-[(tert-butoxy)carbonyl]-5-methyl-1H-indol-2-yl}boronic acid (CAS
475102-14-8, 3.0 g, 10.91 mmol) in toluene (50 mL) and EtOH (12.2
mL) was added aqueous sodium carbonate is solution (2.0M, 14.72 mL,
29.73 mmol). The reaction mixture was degassed with nitrogen and
tetrakis(triphenylphosphine)palladium(0) (0.389 g, 0.33 mmol) was
added. The reaction mixture was heated at 90.degree. C. for 16
hours and then allowed to cool and was diluted with EtOAc, washed
with water and brine. The organics were dried (Na.sub.2SO.sub.4)
and the crude product was purified by column chromatography (silica
gel) eluted with 20% EtOAc in petroleum ether 40-60 to afford the
title compound.
[0334] MS ES.sup.+:309
Intermediate 23
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-3-methyl-1H-i-
ndole
##STR00032##
[0336] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 6-chloropyridazine-4-carboxylic acid
(Intermediate 1; 88 mg, 0.552 mmol) and
1-ethyl-3-methyl-2-(piperidin-3-yl)-1H-indole hemi-formate salt
(Intermediate 24; 132 mg, 0.502 mmol) with the exception that
column chromatography (silica gel) using 0-100% EtOAc in petroleum
ether 40-60 was used in place of solid phase extraction to afford
the title compound.
[0337] MS ES.sup.+:383
Intermediate 24 1-Ethyl-3-methyl-2-(piperidin-3-yl)-1H-indole
hemi-formate salt
##STR00033##
[0339] Prepared as described for
1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemi-formate
(Intermediate 19) from 1-ethyl-3-methyl-2-(pyridin-3-yl)-1H-indole
(Intermediate 25; 1.3 g, 5.51 mmol), except that a solution of HCl
in 1,4-dioxane (4M, 1.37 mL, 5.48 mmol) was used. The crude product
was purified by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% formic acid) to afford the title
compound.
[0340] MS ES.sup.+:243
Intermediate 25 1-Ethyl-3-methyl-2-(pyridin-3-yl)-1H-indole
##STR00034##
[0342] Prepared as described for
1-ethyl-5-methyl-2-(pyridin-3-yl)-1H-indole (Intermediate 20) from
3-methyl-2-(pyridin-3-yl)-1H-indole (Intermediate 26, free-base; 4
g, 19 mmol) and iodoethane (6 g, 38 mmol) except that the reaction
was maintained at 0.degree. C. for 1 hour before being poured onto
ice/water and extracted into DCM. The combined organics were washed
with water and brine and was concentrated in vacuo and the residue
was then partitioned between diethyl ether and brine and then water
and was then purified by column chromatography (silica gel) eluted
with DCM to afford the title compound.
[0343] MS ES.sup.+:237
Intermediate 26 3-Methyl-2-(pyridin-3-yl)-1H-indole
hydrochloride
##STR00035##
[0345] To a stirred solution of crude
3-[1-(2-phenylhydrazin-1-ylidene)propyl]pyridine (Intermediate 27,
not isolated) in EtOH (100 mL) was added a solution of HCl in
1,4-dioxane (4.0M, 37.1 mL, 148.4 mmol) and the reaction mixture
was heated to reflux for 3 hours. The reaction mixture was allowed
to cool to ambient temperature and was poured onto ice. The
resulting precipitate was collected by filtration, washed with THF
and air dried to afford the title compound used in the next step
without further purification.
[0346] MS ES.sup.+:209
Intermediate 27
3-[1-(2-Phenylhydrazin-1-ylidene)propyl]pyridine
##STR00036##
[0348] A stirred solution of 1-(pyridin-3-yl)propan-1-one (CAS
1570-48-5; 5.08 g, 37.6 mmol) and phenyl hydrazine hydrochloride
(5.44 g, 37.6 mmol) in EtOH (100 mL) was heated at reflux for 1
hour to afford the title compound which was used in the next step
without isolation or further purification.
[0349] MS ES.sup.+:226
Intermediate 28
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-5-methyl-1H-i-
ndole
##STR00037##
[0351] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 6-chloropyridazine-4-carboxylic acid
(Intermediate 1; 104 mg, 0.655 mmol) and
1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemi-formate salt
(Intermediate 19; 156 mg, 0.596 mmol) with the exception that
purification was carried out by column chromatography (silica gel)
eluted with 0-100% EtOAc in petroleum ether 40-60 was used in place
of solid phase extraction to afford the title compound.
[0352] MS ES.sup.+:383
Intermediate 29
5-Chloro-2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-i-
ndole
##STR00038##
[0354] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 6-chloropyridazine-4-carboxylic acid
(Intermediate 1; 93 mg, 0.585 mmol) and
5-chloro-1-ethyl-2-(piperidin-3-yl)-1H-indole hemi-formate salt
(Intermediate 30; 150 mg, 0.532 mmol) with the exception that
column chromatography (silica gel) eluted with 0-100% EtOAc in
petroleum ether 40-60 was used in place of solid phase extraction
to afford the title compound.
[0355] MS ES.sup.+:403
Intermediate 30 5-Chloro-1-ethyl-2-(piperidin-3-yl)-1H-indole
hemi-formate
##STR00039##
[0357] To a stirred solution of
5-chloro-1-ethyl-2-(pyridin-3-yl)-1H-indole (Intermediate 31; 500
mg, 1.95 mmol) in absolute EtOH (25 mL) was added HCl (37%, 0.16
mL, 1.95 mmol). The reaction vessel was evacuated and back filled
with nitrogen gas then platinum(IV) oxide (44 mg, 0.195 mmol) was
added and the reaction vessel was evacuated and back filled with
hydrogen gas. The reaction mixture was stirred at ambient
temperature under a hydrogen atmosphere overnight. The reaction
mixture was filtered through diatomaceous earth and concentrated in
vacuo. The crude product was purified by reverse phase preparative
HPLC eluted with acetonitrile/water (with 0.1% formic acid) to
afford the io title compound.
[0358] MS ES.sup.+:263
Intermediate 31 5-Chloro-1-ethyl-2-(pyridin-3-yl)-1H-indole
##STR00040##
[0360] To a stirred suspension of sodium hydride (60% dispersion in
mineral oil, 490 mg, 12.73 mmol) in DMF (30 mL) at 0.degree. C. was
added a solution of 5-chloro-2-(pyridin-3-yl)-1H-indole
(Intermediate 32; 1.94 g, 8.84 mmol) in DMF (20 mL) over 20
minutes. To the stirred mixture was added iodoethane (1.37 mL,
16.97 mmol). After 90 minutes the reaction mixture was allowed to
warm to ambient temperature and was stirred for a further 3 hours.
The reaction mixture was carefully poured onto ice/water and
extracted into DCM. The combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
the title compound which was used in the next step without further
purification.
[0361] MS ES.sup.+:257
Intermediate 32 5-Chloro-2-(pyridin-3-yl)-1H-indole
##STR00041##
[0363] To a stirred solution of tert-butyl
5-chloro-2-(pyridin-3-yl)-1H-indole-1-carboxylate (Intermediate 33;
2.5 g, 7.604 mmol) and anisole (10 mL, 92.01 mmol) in DCM (75 mL)
was added trifluoroacetic acid (15 mL, 196 mmol) and the reaction
was stirred at ambient temperature under a nitrogen atmosphere
overnight. The reaction mixture was concentrated in vacuo and the
crude product was partitioned between EtOAc and saturated aqueous
sodium bicarbonate solution. The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo and
triturated with DCM to afford the title compound which was used in
the next step without further purification.
[0364] MS ES.sup.+:229
Intermediate 33 tert-Butyl
5-chloro-2-(pyridin-3-yl)-1H-indole-1-carboxylate
##STR00042##
[0366] To a stirred solution of 3-iodopyridine (3.15 g, 15.37 mmol)
and {1-[(tert-butoxy)carbonyl]-5-chloro-1H-indol-2-yl}boronic acid
(5.0 g, 16.92 mmol) in toluene (80 mL) and absolute EtOH (19 mL)
under an atmosphere of nitrogen was added sodium carbonate solution
(2 M, 23 mL, 46 mmol). The reaction mixture was degassed by
bubbling nitrogen through it for 10 minutes then
tetrakis(triphenylphosphine)palladium(0) (665 mg, 0.575 mmol) was
added and the reaction mixture was heated at 90.degree. C. for 3.5
hours. The reaction was allowed to cool to ambient temperature and
was diluted in EtOAc and water. The organic phase was separated,
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo and purified by column chromatography (silica
gel) eluted with 5-25% EtOAc in petroleum ether to afford the title
compound.
[0367] MS ES.sup.+:329
Intermediate 34
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-3-methyl-1H-indole
##STR00043##
[0369] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 6-chloropyridazine-4-carboxylic acid
(Intermediate 1; 111 mg, 0.700 mmol) and
3-methyl-2-(piperidin-3-yl)-1H-indole (Intermediate 35; 150 mg,
0.700 mmol) with the exception that reverse phase preparative HPLC
eluted with acetonitrile/water (with 0.1% ammonia) was used in
place of solid phase extraction to afford the title compound.
[0370] MS ES.sup.+:355
Intermediate 35 3-Methyl-2-(piperidin-3-yl)-1H-indole
##STR00044##
[0372] Prepared as described for
1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemi-formate
(Intermediate 19) from 3-methyl-2-(pyridin-3-yl)-1H-indole
hydrochloride (Intermediate 26, 2 g, 8.2 mmol) and platinum(IV)
oxide (0.4 g, 1.76 mmol) except that no HCl was added and the title
compound was isolated by filtration and used without further
purification.
[0373] MS ES.sup.+:215
Intermediate 36 tert-Butyl
N-{4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1-
H-pyrazol-3-yl)carbamate
##STR00045##
[0375] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 1-ethyl-3-methyl-2-(piperidin-3-yl)-1H-indole
hemi-formate salt (Intermediate 24; 132 mg, 0.502 mmol) and
3-{[(tert-butoxy)carbonyl]amino}1-1-methyl-1H-pyrazole-4-carboxylic
acid (Intermediate 17; 0.133 g, 0.552 mmol) in dichloromethane (2
mL), except the work-up was performed as follows:
[0376] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and the organic phase was separated using a
phase separator cartridge. The aqueous phase was extracted with DCM
and the combined organics were concentrated in vacuo to afford the
title compound which was used without further purification.
[0377] MS ES.sup.+:466
Intermediate 37 tert-Butyl
N-{4-[3-(1-ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1-
H-pyrazol-3-yl}carbamate
##STR00046##
[0379] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole
hemi-formate (Intermediate 19; 156 mg, 0.596 mmol) and
3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic
acid (Intermediate 17; 0.158 g, 0.655 mmol) in dichloromethane (2
mL), except the work-up was performed as follows:
[0380] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and the organic phase was separated using a
phase separator cartridge. The aqueous phase was extracted with DCM
and the combined organics were concentrated in vacuo to afford the
title compound which was used without further purification.
[0381] MS ES.sup.+:466
Intermediate 38 tert-Butyl
N-{4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1-
H-pyrazol-3-yl)carbamate
##STR00047##
[0383] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 5-chloro-1-ethyl-2-(piperidin-3-yl)-1H-indole
hemi-formate (Intermediate 30; 150 mg, 0.532 mmol) and
3-{[(tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic
acid (Intermediate 17; 0.141 g, 0.585 mmol) in dichloromethane (2
mL), except the work-up was performed as follows:
[0384] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and the organic phase was separated using a
phase separator cartridge. The aqueous phase was extracted with DCM
and the combined organics were concentrated in vacuo to afford the
title compound which was used without further purification.
[0385] MS ES.sup.+:486
Intermediate 39
3-Chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]pyrida-
zine
##STR00048##
[0387] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from 5-chloro-3-methyl-2-(piperidin-3-yl)pyridine
(Intermediate 40; 0.09 g, 0.427 mmol) and
6-chloropyridazine-4-carboxylic acid (Intermediate 1; 74 mg, 0.470
mmol) in DCM (2 mL), except the work-up was performed as
follows:
[0388] The reaction mixture was diluted in DCM, washed with
saturated aqueous NaHCO.sub.3 and the organic phase was separated
using a phase separator cartridge and concentrated in vacuo and
purified by column chromatography (silica gel) eluted with 0-50%
EtOAc in petroleum ether 40-60 to afford the title compound.
[0389] MS ES.sup.+:351
Intermediate 40 5-Chloro-3-methyl-2-(piperidin-3-yl)pyridine
##STR00049##
[0391] To a stirred solution of
2-(1-benzylpiperidin-3-yl)-5-chloro-3-methylpyridine (Intermediate
41; 0.14 g, 0.465 mmol) and triethylamine (0.097 ml, 0.698 mmol) in
dichloromethane (3 mL) was added ACE-Cl (0.066 ml, 0.605 mmol)
under a nitrogen atmosphere. The reaction was stirred at room
temperature for 1 hour and was then concentrated in vacuo and the
residue taken up in methanol and stirred for 1.5 hours then
concentrated. The crude product was purified by column
chromatography (basic silica) eluted with 0-10% ethyl
acetate/methanol to afford the title compound.
[0392] MS ES.sup.+:211
Intermediate 41
2-(1-Benzylpiperidin-3-yl)-5-chloro-3-methylpyridine
##STR00050##
[0394] A flask charged with platinum(IV) oxide (0.016 g, 0.072
mmol) and
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-3-methylpyridine
(Intermediate 42; 0.215 g, 0.720 mmol) was evacuated and purged
with nitrogen three times. Ethanol (2 mL) and ethyl acetate (2 mL)
were added under reduced pressure and hydrogen was introduced to
the reaction vessel. The suspension was stirred under an atmosphere
of hydrogen for 7 hours. The suspension was filtered through
diatomaceous earth and the filtrate concentrated in vacuo to give
the title compound which was used without further purification.
[0395] MS ES.sup.+:301
Intermediate 42
2-(1-Benzyl-1,2,5,6-tetrahydropyridin-3-yl)-5-chloro-3-methylpyridine
##STR00051##
[0397] Prepared as described for
2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1-methyl-1H-indole
(Intermediate 3) from
1-benzyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridi-
ne (CAS 1313738-80-5; 0.5 g, 1.671 mmol),
2-bromo-5-chloro-3-methylpyridine (CAS 65550-77-8; 0.380 g, 1.838
mmol), tetrakis-(triphenylphosphine)palladium(0) (0.097 g, 0.084
mmol) and potassium carbonate (0.693 g, 5.01 mmol) in 1,4-dioxane
(10 mL) and water (2.5 mL) and irradiation in a microwave at
110.degree. C. for 30 minutes. The workup was performed by diluting
with ethyl acetate, is washing with 2 M NaOH then saturated brine
and purification by column chromatography (basic silica) eluted
with 0-20% ethyl acetate/petroleum ether 40-60 to afford the title
compound.
[0398] MS ES.sup.+:299
Intermediate 43
5-Chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl) pyridine
hydrochloride
##STR00052##
[0400] To a stirred solution of tert-butyl
3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbox-
ylate (Intermediate 44; 0.1 g, 0.25 mmol) in 1,4-dioxane (1 mL) at
0.degree. C. was added a solution of HCl in 1,4-dioxane (4.0 M, 1
mL, 4 mmol) in a dropwise fashion. After 10 minutes the reaction
mixture was allowed to warm and was stirred at ambient temperature
overnight. The reaction mixture was concentrated in vacuo and was
triturated with diethyl ether to afford the title compound which
was used in the next step without further purification.
[0401] MS ES.sup.+:295
Intermediate 44 tert-Butyl
3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbox-
ylate
##STR00053##
[0403] To a stirred solution of tert-butyl
3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-hydroxypiperidine-1-carbox-
ylate (Intermediate 45; 1.4 g, 3.68 mmol) in THF (20 mL) at
0.degree. C. was added sodium hydride (60% dispersion in mineral
oil, 0.22 g, 3.5 mmol) in portions over 15 minutes. To the reaction
mixture was added iodomethane (0.78 g, 5.5 mmol) and the reaction
mixture was allowed to warm to ambient temperature and was stirred
overnight. The reaction was diluted in water and extracted into
EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo
and purified by column chromatography (silica gel) eluted with 20%
EtOAc in hexane to afford the title compound.
[0404] MS ES.sup.+:339 [M--butyl]H.sup.+
Intermediate 45 tert-Butyl
3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-hydroxypiperidine-1-carbox-
ylate
##STR00054##
[0406] To a stirred solution of
2-bromo-5-chloro-3-(trifluoromethyl)pyridine (Intermediate 46; 11.4
g, 43.8 mmol) in toluene (230 mL) at -78.degree. C. under a
nitrogen atmosphere was added n-butyllithium in hexanes solution
(2.5M, 19.3 mL, 48.2 mmol) dropwise over 20 minutes. After 15-20
mins a solution of tert-butyl 3-oxopiperidine-1-carboxylate (CAS
98977-36-7, 9.6 g, 48.1 mmol) in toluene (50 mL) was added over 5
minutes. The solution was stirred at -78.degree. C. for 45 minutes
and was then allowed to warm to ambient temperature for 1 hour. The
solvent was removed in vacuo and the crude product was taken up in
EtOAc and water. The organic phase was removed and the aqueous
phase was extracted with EtOAc and the combined organics were
washed with water and brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo and purified by column chromatography (silica
gel) eluted with 0.2% MeOH/DCM to afford the title compound after
triturating with hexanes. MS ES.sup.+:325 [M--butyl]H.sup.+
Intermediate 46 2-Bromo-5-chloro-3-(trifluoromethyl)pyridine
##STR00055##
[0408] To a stirred solution of
5-chloro-3-(trifluoromethyl)pyridin-2-amine (Intermediate 47; CAS
79456-33-0, 10 g, 50.9 mmol) in aqueous HBr (48%, 56.7 g, 336 mmol)
at -10.degree. C. was added bromine (23.6 g, 147.5 mmol) dropwise
over 20 minutes, followed by a solution of sodium nitrite (10.2 g,
147.8 mmol) in water (18 mL). The reaction was stirred at ambient
temperature for 2 hours and was basified (pH 9-10) and extracted
into diethyl ether. The organic was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo to afford
the title compound without further purification.
[0409] MS ES.sup.+:262
Intermediate 47 5-Chloro-3-(trifluoromethyl)pyridin-2-amine
##STR00056##
[0411] To a stirred solution of 3-(trifluoromethyl)pyridin-2-amine
(CAS 183610-70-0, 25 g, 154 mmol) in DMF (200 mL) under a nitrogen
atmosphere was added N-chlorosuccinimide (21.63 g, 162 mmol) in
portions. The reaction mixture was heated to 60.degree. C. for 1
hour. Thereaction was allowed to cool to ambient temperature and
was concentrated in vacuo, re-dissolved in DCM and passed through a
pad of silica gel. The DCM was removed in vacuo and the crude
product was taken up in diethyl ether, washed with water then
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo
to afford the title compound without further purification.
[0412] MS ES.sup.+:197
Intermediate 48
3-Chloro-5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperid-
ine-1-carbonyl}pyridazine
##STR00057##
[0414] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine
hydrochloride (Intermediate 43; 132 mg, 0.400 mmol) and
6-chloropyridazine-4-carboxylic acid (Intermediate 1; 76 mg, 0.480
mmol) in dichloromethane (1.5 mL), except the work-up was performed
as follows: The reaction mixture was quenched by addition of
saturated aqueous NaHCO.sub.3 and the is aqueous was extracted into
DCM. The combined organics were concentrated in vacuo to afford the
title compound which was used without further purification.
[0415] MS ES.sup.+:435
Intermediate 49
5-Chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine
hydrochloride
##STR00058##
[0417] Prepared as described for
5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine
hydrochloride (Intermediate 43) from tert-butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carboxylate
(Intermediate 50; 820 mg, 2.41 mmol) in 1,4-dioxane (25 mL) using
HCl in 1,4-dioxane solution (4.0 M, 35 mL, 337.4 mmol) to afford
the title compound.
[0418] MS ES.sup.+:241
Intermediate 50 tert-Butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carboxylate
##STR00059##
[0420] Prepared as described for tert-butyl
3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carbox-
ylate (Intermediate 44) from tert-butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-hydroxypiperidine-1-carboxylate
(Intermediate 51; 2.0 g, 6.132 mmol) in THF (140 mL) using sodium
hydride (60% dispersion in mineral oil, 1.1 g, 27.6 mmol) and
iodomethane (1.7 mL, 27.6 mmol). The crude product was purified by
column chromatography (silica gel) eluted with 2-5% EtOAc/petroleum
ether to afford the title compound.
[0421] MS ES.sup.+:341
Intermediate 51 tert-Butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-hydroxypiperidine-1-carboxylate
##STR00060##
[0423] To a stirred solution of 2-bromo-5-chloro-3-methylpyridine
(CAS 65550-77-8, 19.0 g, 92.0 mmol) in diethyl ether (350 mL) at
-70.degree. C. under a nitrogen atmosphere was added n-butyllithium
in hexanes solution (2.5M, 40.5 mL, 101.2 mmol) dropwise over 20
minutes. After 90 minutes a solution of tert-butyl
3-oxopiperidine-1-carboxylate (CAS 98977-36-7, 20.2 g, 101.2 mmol)
in diethyl ether (100 mL) was added dropwise over 25 minutes. The
solution was stirred at -70.degree. C. for 2 hours and was then
allowed to warm to ambient temperature and was stirred overnight.
The reaction mixture was quenched with saturated aqueous NH.sub.4Cl
and was extracted with diethyl ether. The combined organics were
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo and
purified by column chromatography (silica gel) eluted with 2-8%
EtOAc/toluene to afford the title compound.
[0424] MS ES.sup.+:327
Intermediate 52
5-Chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine
hydrochloride
##STR00061##
[0426] Prepared as described for
5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine
hydrochloride (Intermediate 43) from tert-butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carboxylate
(Intermediate 53; 620 mg, 1.89 mmol) in 1,4-dioxane (25 mL) using
HCl in 1,4-dioxane solution (4.0 M, 35 mL, 337.4 mmol) to afford
the title compound.
[0427] MS ES.sup.+:229
Intermediate 53 tert-Butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carboxylate
##STR00062##
[0429] To a stirred solution of tert-butyl
3-(5-chloro-3-methylpyridin-2-yl)-3-hydroxypiperidine-1-carboxylate
(Intermediate 51; 5.0 g, 15.33 mmol) in DCM (250 mL) at -78.degree.
C. under a nitrogen atmosphere was added N,N-diethylaminosuflur
trifluoride (6.1 mL, 45.99 mmol) dropwise . The temperature was
maintained at -70.degree. C. for 5.5 hours and the reaction was
quenched with MeOH and water. The organic phase was separated,
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo and then purified by column chromatography
(silica gel) eluted with 5% EtOAc/toluene to afford the title
compound.
[0430] MS ES.sup.+:273 [M--butyl]H.sup.+
Intermediate 54
3-Chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbo-
nyl]pyridazine
##STR00063##
[0432] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 49; 100 mg, 0.361 mmol) and
6-chloropyridazine-4-carboxylic acid (Intermediate 1; 86 mg, 0.541
mmol) in dichloromethane (2 mL), except the work-up was performed
as follows:
[0433] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and the aqueous was extracted into DCM. The
combined organics were concentrated in vacuo to afford the title
compound which was used without further purification.
[0434] MS ES.sup.+:381
Intermediate 55
3-Chloro-5-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]car-
bonyl}pyridazine
##STR00064##
[0436] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from
5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 52; 100 mg, 0.377 mmol) and
6-chloropyridazine-4-carboxylic acid (Intermediate 1; 90 mg, 0.566
mmol) in dichloromethane (2 mL), except the work-up was performed
as follows:
[0437] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and the aqueous was extracted into DCM. The
combined organics were concentrated in vacuo to afford the title
compound which was used without further purification.
[0438] MS ES.sup.+:369
Intermediate 56 tert-Butyl
N-{4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-
-methyl-1H-pyrazol-3-yl}carbamate
##STR00065##
[0440] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 49; 50 mg, 0.180 mmol) and
3-{[tert-butoxy)carbonyl]amino}1-1-methyl-1H-pyrazole-4-carboxylic
acid (Intermediate 17; 0.057 g, 0.234 mmol) in dichloromethane (1
mL), except the work-up was performed as follows: The reaction
mixture was quenched by addition of saturated aqueous NaHCO.sub.3
and the aqueous was extracted into DCM. The combined organics were
concentrated in vacuo to afford the title compound which was used
without further purification.
[0441] MS ES.sup.+:464
Intermediate 57 tert-Butyl
N-{4-[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1--
methyl-1H-pyrazol-3-yl}carbamate
##STR00066##
[0443] Prepared as described for
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5) from
5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 52; 50 mg, 0.189 mmol) and
3-{[tert-butoxy)carbonyl]amino}-1-methyl-1H-pyrazole-4-carboxylic
acid (Intermediate 17; 0.059 g, 0.245 mmol) in dichloromethane (1
mL), except the work-up was performed as follows:
[0444] The reaction mixture was quenched by addition of saturated
aqueous NaHCO.sub.3 and the aqueous was extracted into DCM. The
combined organics were concentrated in vacuo to afford the title
compound which was used without further purification.
[0445] MS ES.sup.+:452
2. EXAMPLES
Example 1
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-car-
bonyl}pyridin-2-amine (racemic)
##STR00067##
[0447] To a stirred suspension of
2-(dimethylamino)pyridine-4-carboxylic acid (100 mg, 0.602 mmol),
2-(piperidin-3-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole
dihydrochloride (CAS 1185300-76-8, 190 mg, 0.602 mmol) and
triethylamine (0.335 ml, 2.407 mmol) in DCM (6 mL) was added
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50
wt. % solution in EtOAc) (0.791 ml, 0.903 mmol). The reaction was
stirred at ambient temperature overnight. The reaction mixture was
diluted with DCM, washed with water and the solvent was removed in
vacuo. The crude product was purified by column chromatography
(silica gel) eluted with 0-100% ethyl acetate in petroleum ether
40-60 to afford the title compound.
[0448] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.11-1.56
(m, 3H) 1.57-2.18 (m, 7H) 2.82-3.31 (m, 9H) 3.46-3.68 (m, 1H)
4.34-5.00 (m, 2H) 6.40-6.67 (m, 2H) 7.04-7.25 (m, 2H) 7.46-7.76 (m,
2H) 8.03-8.24 (m, 1H)
[0449] MS ES.sup.+:392
Example 2
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-ca-
rbonyl}pyridin-2-amine (enantiomer 1)
##STR00068##
[0451] Chiral separation of
N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1car-
bonyl}pyridin-2-amine (racemic) (Example 1) was performed using
chiral SFC (Waters system fitted with Chiralpak AD-H column
(10.times.250 mm, 5 .mu.m Daicel); 100 mbar CO.sub.2 with 26% EtOH;
40.degree. C.) to afford the title compound as the first eluting
compound.
[0452] MS ES.sup.+:392
[0453] Chiral SFC (Jasco system fitted with Chiralpak AD-H
(4.6.times.100 mm, 5 .mu.m Daicel); 100 mbar CO.sub.2 with 26%
EtOH; 40.degree. C.) Rt=2.6 mins
Example 3
N,N-Dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-ca-
rbonyl}pyridin-2-amine (enantiomer 2)
##STR00069##
[0455] Chiral separation of
N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1car-
bonyl}pyridin-2-amine (racemic) (Example 1) was performed using
chiral SFC (Waters system fitted with Chiralpak AD-H column
(10.times.250 mm, 5 .mu.m Daicel); 100 mbar CO.sub.2 with 26% EtOH;
40.degree. C.) to afford the title compound as the second eluting
compound.
[0456] MS ES.sup.+:392
[0457] Chiral SFC (Jasco system fitted with Chiralpak AD-H
(4.6.times.100 mm, 5 .mu.m Daicel); 100 mbar CO.sub.2 with 26%
EtOH; 40.degree. C.) Rt=6.75 mins
Example 4
N,N-Dimethyl-4-[3-(1-methyl-1H-1,3-benzodiazol-2-yl)piperidine-1-carbonyl]-
pyridin-2-amine
##STR00070##
[0459] To a stirred solution of
1-methyl-2-(piperidin-3-yl)-1H-1,3-benzodiazole (CAS 013-81-2, 50
mg, 0.232 mmol) dissolved in DCM (10 mL) was added
2-(dimethylamino)pyridine-4-carboxylic acid (CAS 77314-81-9, 38.6
mg, 0.232 mmol) followed by HOAt (37.9 mg, 0.279 mmol), EDC (53.4
mg, 0.279 mmol) and triethylamine (0.162 ml, 1.161 mmol). The
reaction mixture was stirred at ambient temperature for 17 hours.
Saturated sodium bicarbonate solution (10 mL) was added and the
mixture was stirred for 30 minutes after which time the phases were
separated using a phase separator cartridge. The organics were
concentrated under vacuum and the residue was dissolved in DMSO and
purified by preparative HPLC to afford the title compound.
[0460] .sup.1H NMR (400 MHz, DCM-d.sub.2) .delta. ppm 1.66-2.28 (m,
4H) 2.90-3.24 (m, 8H) 3.45-3.94 (m, 5H) 4.52-4.91 (m, 1H) 6.39-6.60
(m, 2H) 7.11-7.47 (m, 3H) 7.56-7.75 (m, 1H) 8.05-8.28 (m, 1H)
[0461] MS ES.sup.+:364
Example 5
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,3-
-benzodiazole
##STR00071##
[0463] Prepared as described for
N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-ca-
rbonyl}pyridin-2-amine (Example 1) from
2-(piperidin-3-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole
dihydrochloride (CAS 1185300-76-8, 229 mg, 0.724 mmol) and
6-chloropyridazine-4-carboxylic acid (Intermediate 1; 130 mg, 0.820
mmol) and the reaction was quenched with saturated aqueous
NaHCO.sub.3 and the organic layer was filtered through a phase
separation cartridge and evaporated to dryness. The crude product
was purified using column chromatography (silica gel) eluted with
20-100% ethyl acetate in petroleum ether 40-60 then 0-20% methanol
in ethyl acetate to afford the title compound.
[0464] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.11-2.17
(m, 10H) 3.03-3.62 (obscured m, 3H) 4.03 (m, 1H) 4.21-4.93 (m, 2H)
7.03-7.26 (m, 2H) 7.51-7.76 (m, 2H) 8.01-8.18 (m, 1H) 9.29-9.44 (m,
1H)
[0465] MS ES.sup.+:384
Example 6
N-Methyl-5-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidine-1-carbon-
yl}pyridazin-3-amine
##STR00072##
[0467]
2-[1-(6-Chloropyridazine-4carbonyl)piperidin-3-yl}-1-(propan-2-yl)--
1H-1,3-benzodiazole (Example 5) (161 mg, 0.419 mmol) was dissolved
in methanamine solution (33% in ethanol, 1.97 g, 20.97 mmol) and
was irradiated in a microwave reactor at 150.degree. C. for 1 hour.
The volatile components were removed in vacuo and the crude product
was purified using column chromatography (silica gel) eluted with
20-100% ethyl acetate in petroleum ether 40-60 then 0-40% methanol
in ethyl acetate to afford the title compound.
[0468] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.26-2.17
(m, 10H) 2.70-2.93 (m, 3H) 2.94-3.66 (obscured m, 3H) 4.02-4.14 (m,
1H) 4.33-4.98 (m, 2H) 6.79 (br. s., 1H) 6.91-7.23 (m, 3H) 7.50-7.76
(m, 2H) 8.38-8.77 (m, 1H)
[0469] MS ES.sup.+:379
Example 7
2-[1-(1-Ethyl-1H-pyrazole-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-1,-
3-benzodiazole
##STR00073##
[0471] Prepared as described for
N,N-dimethyl-4-{3-[1-(propan-2-yl)-1H-1,3-benzodiazol-2-yl]piperidin-1-ca-
rbonyl}pyridin-2-amine (Example 1) from
2-(piperidin-3-yl)-1-(propan-2-yl)-1H-1,3-benzodiazole
dihydrochloride (CAS 1185300-76-8, 0.15 g, 0.474 mmol) and
1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.073 g,
0.522 mmol). The reaction was diluted with DCM and quenched with
saturated aqueous NaHCO.sub.3 and the organic layer was filtered
through a phase separation cartridge and evaporated to dryness. The
crude product was purified by column chromatography (silica gel)
eluted with 0-10% methanol in DCM to afford the title compound.
[0472] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.38 (t,
J=7.33 Hz, 3H) 1.47-1.75 (m, 7H) 1.79-2.16 (m, 3H) 2.86-3.19
(obscured m, 3H) 4.15 (q, J=7.07 Hz, 2H) 4.21-4.62 (m, 2H) 4.82
(br. s., 1H) 7.09-7.22 (m, 2H) 7.53-7.61 (m, 1H) 7.63-7.72 (m, 2H)
8.05 (s, 1H)
[0473] MS ES.sup.+:366
Example 8
N,N-Dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2--
amine
##STR00074##
[0475] To a stirred solution of
1-methyl-2-(piperidin-3-yl)-1H-indole (Intermediate 2; 0.02 g,
0.093 mmol) and 2-(dimethylamino)pyridine-4-carboxylic acid
hydrochloride (0.023 g, 0.112 mmol) in DCM (1 mL) was added
triethylamine (0.026 ml, 0.187 mmol) and then
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50
wt. % solution in EtOAc) (0.139 ml, 0.233 mmol). The reaction
mixture was stirred at room temperature. After 80 mins the reaction
was quenched with saturated aqueous NaHCO.sub.3 and was extracted
into DCM. The crude product was purified by reverse phase
preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia)
to afford the title compound.
[0476] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.52-2.00 (m,
4H) 2.75-3.22 (m, 9H) 3.37-3.88 (m, 4H) 4.46-4.85 (m, 1H) 6.21-6.65
(m, 3H) 6.94-7.61 (m, 4H) 8.06-8.24 (m, 1H)
[0477] MS ES.sup.+:363
Example 9
N-Methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-am-
ine
##STR00075##
[0479] To a microwave vial charged with
2-{1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-methyl-1H-indole
(Intermediate 5; 0.037 g, 0.104 mmol) in 1,4-dioxane (2 mL) was
added methanamine [2M solution in THF] (1.043 ml, 2.085 mmol). The
vial was sealed and irradiated in the microwave at 140.degree. C.
for 5 hours and 20 minutes. Additional methanamine [2M solution in
THF] (1.043 ml, 2.085 mmol) and NMP (1 mL) [to aid microwave
absorption] were added and the reaction irradiated in the microwave
at 160.degree. C. for 1 hour. The volatile components were removed
in vacuo and the crude product was purified by reverse phase
preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia)
to afford the title compound.
[0480] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.53-1.93 (m,
4H) 2.79-3.32 (m, 6H) 3.45-3.86 (m, 4H) 4.42-4.80 (m, 1H) 5.43-5.59
(m, 1H) 6.28-6.36 (m, 1H) 6.60-6.73 (m, 1H) 6.94-7.11 (m, 1H)
7.11-7.24 (m, 1H) 7.25-7.43 (m, 1H) 7.45-7.60 (m, 1H) 8.44-8.49 (m,
1H)
[0481] MS ES.sup.+:350
Example 10
4-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridin-2-a-
mine
##STR00076##
[0483] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from 2-(dimethylamino)pyridine-4-carboxylic acid
hydrochloride (0.040 g, 0.197 mmol) and
1-ethyl-2-(piperidin-3-yl)-1H-indole (Intermediate 6; 0.045 g,
0.197 mmol). The reaction was quenched by addition of saturated
aqueous NaHCO.sub.3, extracted with EtOAc and washed with saturated
aqueous NaHCO.sub.3 then brine. The crude product was purified by
reverse phase preparative HPLC eluted with acetonitrile/water (with
0.1% ammonia) to afford the title compound.
[0484] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.07-1.51 (m,
3H) 1.55-1.98 (m, 3H) 2.07-2.31 (m, 1H) 2.66-3.20 (m, 9H) 3.72-4.04
(m, 2H) 4.25-4.42 (m, 1H) 4.65-5.01 (m, 1H) 6.21-6.38 (m, 1H)
6.41-6.62 (m, 2H) 6.95-7.42 (m, 3H) 7.47-7.68 (m, 1H) 8.22 (dd,
J=19.71, 4.80 Hz, 1H)
[0485] MS ES.sup.+:377
Example 11
5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyridazin-3-
-amine
##STR00077##
[0487] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole
(Intermediate 10; 0.042 g, 0.114 mmol) and dimethylamine [2.0M
solution in THF] (1.139 ml, 2.277 mmol) using NMP (1 mL) as the
solvent. The reaction mixture was irradiated in the microwave at
140.degree. C. for 20 minutes to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia).
[0488] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.87-1.40
(m, 3H) 1.59-1.96 (m, 3H) 2.04-2.15 (m, 1H) 2.75-2.97 (m, 1H)
2.99-3.25 (m, 8H) 3.51 (m, 1H) 3.90-4.09 (m, 1H) 4.27 (m, 1H)
4.42-4.72 (m, 1H) 6.17-6.39 (m, 1H) 6.86-7.16 (m, 3H) 7.29-7.54 (m,
2H) 8.54 (s, 1H)
[0489] MS ES.sup.+:m/z 378
Example 12
5-[3-(1-Ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyridazin-3-ami-
ne
##STR00078##
[0491] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-indole
(Intermediate 10; 0.042 g, 0.114 mmol) and methanamine [2M solution
in THF] (2.278 ml, 4.556 mmol) using NMP (1 mL) as the solvent and
irradiated in the microwave at 140.degree. C. for 2 hours 20
minutes to afford the title is compound after purification by
reverse phase preparative HPLC eluted with acetonitrile/water (with
0.1% ammonia).
[0492] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.91-1.39
(m, 3H) 1.56-1.95 (m, 3H) 1.99-2.18 (m, 1H) 2.74-2.93 (m, 4H)
2.97-3.12 (m, 1H) 3.12-3.26 (m, 1H) 3.46-3.61 (m, 1H) 3.91-4.10 (m,
1H) 4.16-4.33 (m, 1H) 4.43-4.69 (m, 1H) 6.17-6.38 (m, 1H) 6.69-6.83
(m, 1H) 6.90-7.17 (m, 3H) 7.28-7.56 (m, 2H) 8.49 (d, J=7.07 Hz,
1H)
[0493] MS ES.sup.+:364
Example 13
N,N-Dimethyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyr-
idazin-3-amine
##STR00079##
[0495] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-in-
dole (Intermediate 11; 0.065 g, 0.170 mmol) and dimethylamine [2.0M
solution in THF] (1.698 ml, 3.40 mmol) using NMP (1 mL) as the
solvent. The reaction mixture was irradiated in the microwave at
140.degree. C. for 20 minutes to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia).
[0496] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.02-1.50
(m, 3H) 1.54-1.96 (m, 6H) 2.02-2.19 (m, 1H) 2.76-2.95 (m, 1H)
3.03-3.22 (m, 8H) 3.38-3.62 (m, 1H) 4.18-4.91 (m, 2H) 6.11-6.34 (m,
1H) 6.86-7.17 (m, 3H) 7.35-7.66 (m, 2H) 8.54 (d, J=1.01 Hz, 1H)
[0497] MS ES.sup.+:392
Example 14
N-Methyl-5-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}pyridaz-
in-3-amine
##STR00080##
[0499] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-(propan-2-yl)-1H-in-
dole (Intermediate 11; 0.065 g, 0.170 mmol) and methanamine [2M
solution in THF] (1.698 ml, 3.40 mmol) using NMP (1 mL) as the
solvent and irradiated in the microwave at 140.degree. C. for 2
hours and 20 minutes. Additional methanamine [2M solution in THF]
(1.698 ml, 3.40 mmol) was added and the reaction mixture was
irradiated at 140.degree. C. for another 1 hour to afford the title
compound after purification by reverse phase preparative HPLC
eluted with acetonitrile/water (with 0.1% ammonia).
[0500] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.07-1.51
(m, 3H) 1.54-1.95 (m, 6H) 2.02-2.20 (m, 1H) 2.75-2.97 (m, 4H)
2.98-3.24 (m, 2H) 3.44-3.63 (m, 1H) 4.22-4.91 (m, 2H) 6.14-6.33 (m,
1H) 6.72-6.86 (m, 1H) 6.86-7.14 (m, 3H) 7.36-7.67 (m, 2H) 8.40-8.52
(m, 1H)
[0501] MS ES.sup.+:378
Example 15
2-{1-[(1-Ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-1-(propan-2-yl)-1H-
-indole
##STR00081##
[0503] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from 1-ethyl-1H-pyrazole-4-carboxylic acid (CAS
400858-54-0, 0.033 g, 0.238 mmol) and
2-(piperidin-3-yl)-1-(propan-2-yl)-1H-indole (Intermediate 12;
0.048 g, 0.198 mmol). The crude reaction mixture was extracted into
EtOAc and purified by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia) to afford the title
compound.
[0504] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.26-1.91
(m, 12H) 2.01-2.18 (m, 1H) 2.5-3.4 (br., 3H) 4.05-4.20 (m, 2H)
4.21-4.99 (br., 3H) 6.26 (s, 1H) 6.85-7.00 (m, 1H) 7.01-7.08 (m,
1H) 7.47 (d, J=7.58 Hz, 1H) 7.57 (d, J=8.08 Hz, 1H) 7.70 (s, 1H)
8.11 (br. s., 1H)
[0505] .sup.1H NMR (300 MHz, 90.degree. C., DMSO-d.sub.6) .delta.
ppm 1.41 (t, J=7.27 Hz, 3H) 1.55 (d +d, J=6.89, 6H) 1.59-1.94 (m,
3H) 2.07-2.21 (m, 1H) 2.9-3.2 (m, 3H) 4.16 (q, J=7.18 Hz, 2H)
4.23-4.53 (m, 2H) 4.65-4.82 (m, 1H) 6.28 (s, 1H) 6.92-7.00 (m, 1H)
7.01-7.10 (m, 1H) 7.47 (d, J=7.74 Hz, 1H) 7.54 (d, J=8.31 Hz, 1H)
7.65 (s, 1H) 8.00 (s, 1H)
[0506] MS ES.sup.+:365
Example 16
1-Methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-carbonyl}-1H-pyraz-
ol-3-amine
##STR00082##
[0508] To a stirred suspension of tert-butyl
N-(1-methyl-4-{3-[1-(propan-2-yl)-1H-indol-2-yl]piperidine-1-carbonyl}-1H-
-pyrazol-3-yl)carbamate (Intermediate 16; 0.072 g, 0.155 mmol) in
methanol (1 mL) was added HCl [4.0 M in dioxane] (0.116 ml, 0.464
mmol). The reaction mixture was stirred at ambient temperature
overnight. LCMS analysis showed that the reaction had not reached
completion so the reaction mixture was concentrated in vacuo and
re-dissolved in methanol (1 mL) and more HCl [4.0 M in dioxane]
(0.116 ml, 0.464 mmol) was added. The reaction mixture was stirred
at ambient temperature overnight. This process was repeated one
more time until the reaction had reached completion. The volatile
components were removed in vacuo and partitioned between DCM and
saturated aqueous NaHCO.sub.3. The organic phase was removed using
a phase separator cartridge and the aqueous phase was extracted
with more DCM. The organics were combined and the crude product was
purified by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia) to afford the title
compound.
[0509] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.55 (m, 6H)
1.60-1.86 (m, 3H) 2.04-2.15 (m, 1H) 2.75-3.14 (m, 3H) 3.26-3.58 (m,
3H) 4.27 (m, 1H) 4.45 (m, 1H) 4.73 (m, 1H) 5.15 (s, 2H) 6.26 (s,
1H) 6.91-7.00 (m, 1H) 7.01-7.09 (m, 1H) 7.47 (d, J=7.83 Hz, 1H)
7.58 (d, J=8.08 Hz, 1H) 7.76 (s, 1H)
[0510] MS ES.sup.+:366
Example 17
1-Ethyl-2-{1-[(1-ethyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-5-methyl-1-
H-indole
##STR00083##
[0512] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
1-ethyl-5-methyl-2-(piperidin-3-yl)-1H-indole hemi-formate
(Intermediate 19; 0.0782 g, 0.298 mmol) and
1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.046 g,
0.328 mmol) in DCM (1 mL) with an additional step, whereby the
crude product after work-up was passed through a pre-equlibrated
SCX-2 (1 g) cartridge and was washed through with DCM before being
purified by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia) to afford the title
compound.
[0513] .sup.1H NMR (300 MHz, CD.sub.3CN) .delta. ppm 1.26 (br. m,
3H) 1.44 (t, J=7.27 Hz, 3H) 1.56-1.92 (m, 3H) 2.17 (obscured, s,
1H) 2.41 (s, 3H) 2.51-3.51 (br. m, 3H) 4.16 (q, J=7.11 Hz, 4H) 4.35
(br. m, 2H) 6.23 (s, 1H) 6.98 (d, J=8.31 Hz, 1H) 7.17-7.37 (m, 2H)
7.65 (s, 1H) 7.80 (br. s, 1H)
[0514] MS ES.sup.+:365
Example 18
5-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrida-
zin-3-amine
##STR00084##
[0516] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-3-methyl-1H-i-
ndole (Intermediate 23; 0.075 g, 0.196 mmol) and methanamine [2 M
solution in THF] (3.92 ml, 7.84 mmol) using NMP (1 mL) as the
solvent and irradiated in the microwave at 140.degree. C. for 4
hours to afford the title compound after purification by reverse
phase preparative HPLC eluted with acetonitrile/water (with 0.1%
ammonia).
[0517] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.03-1.41 (m,
3H) 1.59-1.85 (m, 1H) 1.90-2.30 (obscured, m, 3H) 2.31-2.48 (m, 3H)
2.80-3.77 (m, 7H) 4.00-4.35 (m, 2H) 4.54-4.79 (m, 1H) 5.46-5.63 (m,
1H) 6.61-6.78 (m, 1H) 6.88-7.59 (m, 4H) 8.40-8.55 (m, 1H)
[0518] MS ES.sup.+:378
Example 19
5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrida-
zin-3-amine
##STR00085##
[0520] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-5-methyl-1H-i-
ndole (Intermediate 28; 0.0575 g, 0.150 mmol) and methanamine [2M
solution in THF] (3.00 ml, 6.01 mmol) using NMP (1 mL) as the
solvent and irradiated in the microwave at 140.degree. C. for 4
hours to afford the title compound after purification by reverse
phase preparative HPLC eluted with acetonitrile/water (with 0.1%
ammonia).
[0521] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 0.95-1.45 (m,
3H) 1.56-1.95 (m, 4H) 2.31-2.46 (m, 3H) 2.75-3.26 (m, 6H) 3.57-3.76
(m, 1H) 3.86-4.34 (m, 2H) 4.50-4.75 (m, 1H) 4.80-5.60 (m, 1H)
6.12-6.31 (m, 1H) 6.55-6.77 (m, 1H) 6.86-7.06 (m, 1H) 7.12-7.37 (m,
2H) 8.36-8.53 (m, 1H)
[0522] MS ES.sup.+:378
Example 20
5-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N-methylpyrida-
zin-3-amine
##STR00086##
[0524] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
5-chloro-2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-i-
ndole (Intermediate 29; 0.062 g, 0.154 mmol) and methanamine [2M
solution in THF] (3.07 ml, 6.15 mmol) using NMP (1 mL) as the
solvent and irradiated in the microwave at 140.degree. C. for 4
hours to afford the title compound after purification by reverse
phase preparative HPLC eluted with acetonitrile/water (with 0.1%
ammonia).
[0525] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.02-1.41 (m,
3H) 1.52-1.90 (m, 3H) 2.11-2.17 (obscured m, 1H) 2.74-3.28 (m, 6H)
3.67 (m, 1H) 3.86-4.39 (m, 2H) 4.48-4.78 (m, 1H) 5.45-5.66 (m, 1H)
6.19-6.39 (m, 1H) 6.58-6.80 (m, 1H) 6.96-7.20 (m, 1H) 7.24-7.43 (m,
1H) 7.43-7.62 (m, 1H) 8.31-8.57 (m, 1H)
[0526] MS ES.sup.+:398
Example 21
5-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpy-
ridazin-3-amine
##STR00087##
[0528] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-5-methyl-1H-i-
ndole (Intermediate 28; 0.0575 g, 0.150 mmol) and dimethylamine
[2.0M in THF] (1.502 ml, 3.00 mmol) using NMP (1 mL) as the solvent
and irradiated in the microwave at 140.degree. C. for 30 minutes.
Purification by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia) afforded the title
compound.
[0529] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 0.96-1.45 (m,
3H) 1.53-1.95 (m, 3H) 2.08-2.22 (obscured m, 1H) 2.32-2.46 (m, 3H)
2.75-3.28 (m, 9H) 3.51-3.72 (m, 1H) 3.79-4.34 (m, 2H) 4.46-4.80 (m,
1H) 6.10-6.33 (m, 1H) 6.76-7.04 (m, 2H) 7.11-7.38 (m, 2H) 8.37-8.54
(m, 1H)
[0530] MS ES.sup.+:392
Example 22
5-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-N,N-dimethylpy-
ridazin-3-amine
##STR00088##
[0532] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
5-chloro-2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-1-ethyl-1H-i-
ndole (Intermediate 29; 0.031 g, 0.077 mmol) and dimethylamine
[2.0M in THF] (0.769 ml, 1.537 mmol) using NMP (1 mL) as the
solvent and irradiated in the microwave at 140.degree. C. for 1
hour to afford the title compound after purification by reverse
phase preparative HPLC eluted with acetonitrile/water (with 0.1%
ammonia).
[0533] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.00-1.47 (m,
3H) 1.57-1.94 (m, 3H) 2.18 (obscured m, 1H) 2.76-3.27 (m, 9H)
3.54-3.75 (m, 1H) 3.84-4.37 (m, 2H) 4.48-4.80 (m, 1H) 6.19-6.40 (m,
1H) 6.74-6.96 (m, 1H) 7.12 (m, 1H) 7.24-7.43 (m, 1H) 7.44-7.59 (m,
1H) 8.39-8.55 (m, 1H)
[0534] MS ES.sup.+:412
Example 23
N-Methyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-am-
ine
##STR00089##
[0536] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-chloropyridazine-4-carbonyl)piperidin-3-yl]-3-methyl-1H-indole
(Intermediate 34; 0.034 g, 0.096 mmol) and methanamine [2M solution
in THF] (1.916 ml, 3.83 mmol) using NMP (1 mL) as the solvent and
irradiated in a microwave at 140.degree. C. for 1 hour. Additional
methanamine [2M solution in THF] (1.916 ml, 3.83 mmol) was added
and the reaction was irradiated in the microwave at 140.degree. C.
for a further 5 hours to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile / water (with 0.1% ammonia).
[0537] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.77 (m, 2H)
2.15-2.36 (obscured m, 5H) 2.74-3.06 (m, 4H) 3.08-3.28 (m, 2H)
3.52-3.74 (m, 1H) 4.51-4.70 (m, 1H) 5.35-5.62 (m, 1H) 6.59-6.79 (m,
1H) 6.89-7.17 (m, 2H) 7.20-7.55 (m, 2H) 8.39-8.54 (m, 1H) 8.89-9.16
(m, 1H)
[0538] MS ES.sup.+:350
Example 24
N,N-Dimethyl-5-[3-(3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin--
3-amine
##STR00090##
[0540] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
2-[1-(6-Chloropyridazine-4-carbonyl)piperidin-3-yl]-3-methyl-1H-indole
(Intermediate 34; 0.034 g, 0.096 mmol) and dimethylamine [2M
solution in THF] (1.916 ml, 3.83 mmol) using NMP (1 mL) as the
solvent and irradiated in a microwave at 140.degree. C. for 30
minutes to afford the title compound after purification using
reverse phase preparative HPLC eluted with acetonitrile/water (with
0.1% ammonia) followed by a second purification using reverse phase
preparative HPLC eluted with acetonitrile/water (with 0.1% formic
acid).
[0541] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.53-1.84 (m,
2H) 2.00-2.39 (m, 5H) 2.78-3.30 (m, 9H) 3.46-3.74 (m, 1H) 4.51-4.73
(m, 1H) 6.76-6.93 (m, 1H) 6.94-7.16 (m, 2H) 7.23-7.55 (m, 2H)
8.32-8.56 (m, 1H) 8.89-9.22 (m, 1H)
[0542] MS ES.sup.+:364
Example 25
4-[3-(1-Ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-py-
razol-3-amine
##STR00091##
[0544] To a stirred solution of tert-butyl
N-{4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1-
H-pyrazol-3-yl)carbamate (Intermediate 36; 234 mg, carried through
from previous step without purification) in DCM (1mL) was added TFA
(0.1 ml, 1.298 mmol). The reaction mixture was stirred at ambient
temperature for 90 hours. The volatile components were removed in
vacuo and the crude product was purified by reverse phase
preparative HPLC eluted with acetonitrile/water (with 0.1% ammonia)
to afford the title compound.
[0545] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 0.94-1.31 (m,
3H) 1.53-1.91 (obscured m, 2H) 2.01-2.47 (obscured m, 5H) 3.01-3.15
(m, 2H) 3.25-3.41 (m, 1H) 3.63 (s, 3H) 4.22 (q, J=7.16 Hz, 2H)
4.36-4.51 (m, 2H) 4.75 (br. s., 2H) 6.96-7.08 (m, 1H) 7.15 (t,
J=7.20 Hz, 1H) 7.33 (d, J=8.08 Hz, 1H) 7.42-7.54 (m, 2H)
[0546] MS ES.sup.+:366
Example 26
4-[3-(1-Ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-py-
razol-3-amine
##STR00092##
[0548] Prepared as described for
4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine (Example 25) from tert-butyl
N-{4-[3-(1-ethyl-5-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1-
H-pyrazol-3-yl}carbamate (Intermediate 37; 277 mg, carried through
from previous step without purification) to afford the title
compound.
[0549] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.22-1.47 (m,
3H) 1.55-1.91 (m, 3H) 2.04-2.13 (m, 1H) 2.37-2.57 (m, 3H) 2.87-3.20
(m, 3H) 3.64 (s, 3H) 4.20 (q, J=7.07 Hz, 2H) 4.30-4.41 (m, 1H)
4.45-4.59 (m, 1H) 4.74 (br. s., 2H) 6.23 (s, 1H) 6.98 (d, J=8.34
Hz, 1H) 7.20-7.35 (m, 2H) 7.48 (s, 1H)
[0550] MS ES.sup.+:366
Example 27
4-[3-(5-Chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-py-
razol-3-amine
##STR00093##
[0552] Prepared as described for
4-[3-(1-ethyl-3-methyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1H-p-
yrazol-3-amine (Example 25) from tert-butyl
N-{4-[3-(5-chloro-1-ethyl-1H-indol-2-yl)piperidine-1-carbonyl]-1-methyl-1-
H-pyrazol-3-yl)carbamate (Intermediate 38; 259 mg, carried through
from previous step without purification) to afford the title
compound.
[0553] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.31 (t,
J=7.20 Hz, 3H) 1.60-1.93 (m, 3H) 2.08-2.13 (obscured m, 1H)
2.87-3.19 (m, 3H) 3.64 (s, 3H) 4.23 (q, J=7.07 Hz, 2H) 4.28-4.39
(m, 1H) 4.46-4.58 (m, 1H) 4.75 (br. s., 2H) 6.32 (s, 1H) 7.13 (dd,
J=8.72, 1.89 Hz, 1H) 7.38 (d, J=8.84 Hz, 1H) 7.49 (s, 1H) 7.53 (d,
J=2.02 Hz, 1H)
[0554] MS ES.sup.+:386
Example 28
5-[3-(5-Chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]-N,N-dimethylpyr-
idazin-3-amine
##STR00094##
[0556] A solution of
3-chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)piperidine-1-carbonyl]pyrida-
zine (Intermediate 39; 0.063 g, 0.179 mmol) and dimethylamine (2 M
in THF) (1.794 ml, 3.59 mmol) in butan-1-ol (2 mL) was heated in a
sealed tube to 135.degree. C. for 2 hours. The solution was
concentrated in vacuo and the crude product was purified by reverse
phase preparative HPLC eluted with acetonitrile / water (with 0.1%
ammonia) to afford the title compound.
[0557] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.56-1.97
(m, 4H) 2.17-2.42 (m, 3H) 2.78-3.19 (m, 8H) 3.33-3.56 (m, 2H)
4.43-4.56 (m, 1H) 7.03-7.09 (m, 1H) 7.61-7.81 (m, 1H) 8.30-8.54 (m,
2H)
[0558] MS ES.sup.+:360
Example 29
4-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carb-
onyl}-N-methylpyridin-2-amine formate
##STR00095##
[0560] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine
(Intermediate 43 (free base); 0.010 g, 0.026 mmol) and
2-(methylamino)pyridine-4-carboxylic acid hydrochloride hemi
hydrate (CAS 876717-53-2, 7.75 mg, 0.039 mmol) in DCM (0.5 mL),
except that the reaction was quenched by diluting in MeOH (3 mL)
and stirred for 1 hour. The crude product was purified by reverse
phase preparative HPLC eluted with acetonitrile / water (with 0.1%
formic acid) to afford the title compound.
[0561] .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. ppm
1.78-2.11 (m, 3H) 2.22-2.46 (m, 1H) 2.87-3.24 (m, 7H) 3.40-4.95
(obscured m, 3H) 6.47-6.68 (m, 2H) 7.84-8.35 (m, 3H) 8.81 (dd,
J=13.77, 1.89 Hz, 1H)
[0562] MS ES.sup.+:429
Example 30
5-({3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidin-1-yl}c-
arbonyl)-N-methylpyridazin-3-amine
##STR00096##
[0564] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
3-chloro-5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperid-
ine-1-carbonyl}pyridazine (Intermediate 48; 0.08 g, 0.184 mmol) and
methanamine [2 M solution in THF] (3.68 ml, 7.35 mmol) using NMP (1
mL) as the solvent and irradiated in the microwave at 140.degree.
C. for 2.5 hours to afford the title compound after purification by
reverse phase preparative HPLC eluted with acetonitrile/water (with
0.1% ammonia).
[0565] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.48-2.34
(obscured m, 4H) 2.83-3.13 (m, 7H) 3.20-4.88 (m, 3H) 5.36-5.54 (m,
1H) 6.53-6.65 (m, 1H) 8.04-8.24 (m, 1H) 8.28-8.41 (m, 1H) 8.65-8.76
(m, 1H)
[0566] MS ES.sup.+:430
Example 31
5-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carb-
onyl}-N,N-dimethylpyridazin-3-amine
##STR00097##
[0568] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
3-chloro-5-{3-[5-chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperid-
ine-1-carbonyl}pyridazine (Intermediate 48; 0.08 g, 0.184 mmol) and
dimethylamine [2 M solution in THF] (3.68 ml, 7.35 mmol) using NMP
(1 mL) as the solvent and irradiated in the microwave at
140.degree. C. for 1 hour to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile / water (with 0.1% ammonia).
[0569] .sup.1H NMR (300 MHz, CD.sub.3CN) .delta. ppm 1.52-2.44
(obscured m, 4H) 2.84-3.23 (m, 10H) 3.23-4.97 (m, 3H) 6.77-6.90 (m,
1H) 8.05-8.31 (m, 1H) 8.34-8.48 (m, 1H) 8.69-8.85 (m, 1H)
[0570] MS ES.sup.+:444
Example 32
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3--
(trifluoromethyl)pyridine
##STR00098##
[0572] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine
hydrochloride (Intermediate 43; 66.2 mg, 0.2 mmol) and
1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.031 g,
0.220 mmol) in DCM (0.5 mL) to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia).
[0573] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.44 (t,
J=7.20 Hz, 3H) 1.69-2.71 (obscured br. m, 4H) 2.84-3.64 (br. m, 5H)
4.03-5.04 (br. m +q, 4H) 7.62 (br. s., 1H) 7.79 (br. s., 1H) 8.22
(br. s., 1H) 8.77 (m, 1H)
[0574] MS ES.sup.+:417
Example 33
4-{3-[5-Chloro-3-(trifluoromethyl)pyridin-2-yl]-3-methoxypiperidine-1-carb-
onyl}-N,N-dimethylpyridin-2-amine
##STR00099##
[0576] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-(trifluoromethyl)pyridine
hydrochloride (Intermediate 43; 0.050 g, 0.151 mmol) and
2-(dimethylamino)pyridine-4-carboxylic acid hydrochloride (0.046 g,
0.226 mmol) in DCM (1 mL) except purified by reverse phase
preparative HPLC eluted with acetonitrile/water (with 0.1% formic
acid) to afford the title compound.
[0577] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.48-2.67
(obscured m, 4H) 2.90-3.16 (m, 9H) 3.19-4.96 (m, 4H) 6.35-6.59 (m,
2H) 8.00-8.32 (m, 2H) 8.68-8.83 (m, 1H)
[0578] MS ES.sup.+:443
Example 34
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-met-
hylpyridin-2-amine
##STR00100##
[0580] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 49; 0.050 g, 0.180 mmol) and
2-(methylamino)pyridine-4-carboxylic acid hydrochloride hemi
hydrate (CAS 876717-53-2, 0.053 g, 0.271 mmol) in DCM (1 mL) to
afford the title compound.
[0581] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.37-1.90
(obscured m, 2H) 1.96-2.28 (obscured m, 2H) 2.35-2.52 (m, 3H)
2.69-3.03 (m, 6H) 3.13-3.40 (m, 2H) 3.44-4.83 (m, 2H) 5.04-5.24 (m,
1H) 6.16-6.43 (m, 2H) 7.34-7.60 (m, 1H) 7.96 (m, 1H) 8.17-8.33 (m,
1H)
[0582] MS ES.sup.+:375
Example 35
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-meth-
ylpyridin-2-amine
##STR00101##
[0584] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 52; 0.050 g, 0.189 mmol) and
2-(methylamino)pyridine-4-carboxylic acid hydrochloride hemi
hydrate (CAS 876717-53-2, 0.056 g, 0.283 mmol) in DCM (1 mL) to
afford the title compound after purification by reverse phase
preparative HPLC eluted with acetonitrile/water (with 0.1% formic
acid).
[0585] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.59-1.97
(obscured m, 3H) 2.13-2.29 (obscured m, 1H) 2.43-2.59 (m, 3H)
2.77-4.94 (m, 7H) 5.17-5.39 (m, 1H) 6.31-6.41 (m, 1H) 6.44-6.56 (m,
1H) 7.53-7.75 (m, 1H) 7.94-8.15 (m, 1H) 8.25-8.45 (m, 1H) MS
ES.sup.+:363
Example 36
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N-met-
hylpyridazin-3-amine
##STR00102##
[0587] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
3-chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbo-
nyl]pyridazine (Intermediate 54; 0.057 g, 0.150 mmol) and
methanamine [2 M solution in THF] (4.50 ml, 9.00 mmol) using NMP
(1.5 mL) as the solvent and irradiated in the microwave at
140.degree. C. for 3 hours to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia).
[0588] .sup.1H NMR (400 MHz, Methanol-d.sub.4) .delta. ppm
1.55-2.06 (m, 3H) 2.14-2.67 (m, 4H) 2.89-3.28 (m, 7H) 3.38-4.97 (m,
3H) 6.76-6.92 (m, 1H) 7.48-7.73 (m, 1H) 8.30-8.45 (m, 2H).
[0589] MS ES.sup.+:376
Example 37
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-N,N-d-
imethylpyridazin-3-amine
##STR00103##
[0591] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
3-chloro-5-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbo-
nyl]pyridazine (Intermediate 54; 0.057 g, 0.150 mmol) and
dimethylamine [2 M solution in THF] (6.3 ml, 12.6 mmol) using NMP
(1.5 mL) as the solvent and irradiated in the microwave at
140.degree. C. for 90 minutes to afford the title compound after
purification by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia).
[0592] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.51-2.64
(obscured m, 7H) 2.87-4.97 (m, 13H) 6.75-6.90 (m, 1H) 7.46-7.69 (m,
1H) 8.30-8.48 (m, 2H)
[0593] MS ES.sup.+:390
Example 38
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N-meth-
ylpyridazin-3-amine
##STR00104##
[0595] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
3-chloro-5-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]car-
bonyl }pyridazine (Intermediate 55; 0.087 g, 0.236 mmol) and
methanamine [2 M solution in THF] (4.71 ml, 9.43 mmol) using NMP (1
mL) as the solvent and irradiated in the microwave at 140.degree.
C. for 2.5 hours to afford the title compound after purification by
reverse phase preparative HPLC eluted with acetonitrile/water (with
0.1% ammonia).
[0596] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.63-2.57
(obscured m, 7H) 2.88-4.93 (m, 7H) 5.49-5.65 (m, 1H) 6.69 (m, 1H)
7.55-7.73 (m, 1H) 8.25-8.49 (m, 2H)
[0597] MS ES.sup.+:364
Example 39
5-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-N,N-di-
methylpyridazin-3-amine
##STR00105##
[0599] Prepared as described for
N-methyl-5-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridazin-3-a-
mine (Example 9) from
3-chloro-5-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]car-
bonyl}pyridazine (Intermediate 55; 0.087 g, 0.236 mmol) and
dimethylamine [2 M solution in THF] (4.7 ml, 9.4 mmol) using NMP (1
mL) as the solvent and irradiated in the microwave at 140.degree.
C. for 1 hour to afford the title compound after purification by
reverse phase preparative HPLC eluted with acetonitrile / water
(with 0.1% ammonia).
[0600] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.62-2.59
(obscured m, 7H) 2.90-4.97 (m, 10H) 6.77-6.90 (m, 1H) 7.55-7.73 (m,
1H) 8.26-8.48 (m, 2H)
[0601] MS ES.sup.+:378
Example 40
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-methoxypiperidin-3-yl]-3--
methylpyridine
##STR00106##
[0603] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-methoxypiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 49; 0.050 g, 0.180 mmol) and
1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.033 g,
0.234 mmol) in DCM (1 mL) to afford the title compound.
[0604] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.45 (t,
J=7.33 Hz, 3H) 1.61-2.69 (obscured br. m, 7H) 2.75-3.68 (br. m, 5H)
4.04-5.02 (br. m +q, 4H) 7.44-7.68 (m, 2H) 7.79 (s, 1H) 8.29-8.44
(m, 1H)
[0605] MS ES.sup.+:363
Example 41
5-Chloro-2-[1-(1-ethyl-1H-pyrazole-4-carbonyl)-3-fluoropiperidin-3-yl]-3-m-
ethylpyridine
##STR00107##
[0607] Prepared as described for
N,N-dimethyl-4-[3-(1-methyl-1H-indol-2-yl)piperidine-1-carbonyl]pyridin-2-
-amine (Example 8) from
5-chloro-2-(3-fluoropiperidin-3-yl)-3-methylpyridine hydrochloride
(Intermediate 52; 0.050 g, 0.189 mmol) and
1-ethyl-1H-pyrazole-4-carboxylic acid (CAS 400858-54-0, 0.034 g,
0.245 mmol) in DCM (1 mL) to afford the title compound.
[0608] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.43 (t,
J=7.07 Hz, 3H) 1.66-2.02 (obscured m, 2H) 2.23-2.62 (m, 5H)
2.68-4.05 (br. m, 2H) 4.16 (q, J=6.82 Hz, 2H) 4.24-5.16 (br. m, 2H)
7.54-7.70 (m, 2H) 7.80 (br. s., 1H) 8.37 (s, 1H)
[0609] MS ES.sup.+:351
Example 42
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-met-
hyl-1H-pyrazol-3-amine
##STR00108##
[0611] To a stirred solution of tert-butyl
N-{4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-
-methyl-1H-pyrazol-3-yl }carbamate (Intermediate 56; 84 mg, 0.18
mmol) in DCM (1 mL) was added TFA (0.25 ml, 3.24 mmol). The
reaction was stirred at ambient temperature for 140 minutes and
then quenched with saturated aqueous NaHCO.sub.3 The resulting
mixture was extracted into DCM, then loaded onto a strong cation
exchange cartridge (SCX-2, 1 g), washed with DCM/MeOH (4:1) and
eluted off with DCM/[2M NH.sub.3 in MeOH] (4:1). The crude product
was purified by reverse phase preparative HPLC eluted with
acetonitrile/water (with 0.1% ammonia) to afford the title
compound.
[0612] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.56-2.37
(obscured m, 4H) 2.51 (s, 3H) 2.95 (s, 3H) 3.02-3.17 (m, 1H)
3.37-3.53 (m, 1H) 3.65 (s, 3H) 4.12-4.27 (m, 1H) 4.58-4.84 (m, 3H)
7.50 (s, 1H) 7.62 (d, J=2.02 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H)
[0613] MS ES.sup.+:364
Example 43
4-[3-(5-Chloro-3-methylpyridin-2-yl)-3-fluoropiperidine-1-carbonyl]-1-meth-
yl-1H-pyrazol-3-amine
##STR00109##
[0615] Prepared as described for
4-[3-(5-chloro-3-methylpyridin-2-yl)-3-methoxypiperidine-1-carbonyl]-1-me-
thyl-1H-pyrazol-3-amine (Example 42) from tert-butyl
N-(4-{[3-(5-chloro-3-methylpyridin-2-yl)-3-fluoropiperidin-1-yl]carbonyl}-
-1-methyl-1H-pyrazol-3-yl)carbamate (Intermediate 57; 0.076 g,
0.168 mmol) using TFA (0.25 ml, 3.24 mmol) in DCM (1 mL) to afford
the title compound.
[0616] .sup.1H NMR (400 MHz, CD.sub.3CN) .delta. ppm 1.68-2.03
(obscured m, 3H) 2.25-2.34 (m, 1H) 2.40-2.53 (m, 3H) 3.04 (br. s.,
1H) 3.63 (s, 4H) 4.33-4.83 (m, 4H) 7.47 (s, 1H) 7.67 (s, 1H) 8.38
(s, 1H)
[0617] MS ES.sup.+:352
3. BIOLOGICAL ASSAY
[0618] Prokineticin receptor 1 (PKR1) antagonists may be
functionally assessed by measurement of change in intracellular
calcium levels induced by Gq mediated increase in inositol
triphosphate (IP3) levels. The ability of a compound to block the
intracellular release of calcium mediated by PK1 in RBL2H3 cells
expressing human PKR1 receptors is determined as a measure of the
compound's antagonist activity in vitro.
[0619] Approximately 10,000 cells per assay well are seeded in
normal culture medium in a 384 well plate (Corning). Twenty-four
hours after seeding, the cells are loaded with a calcium sensitive
fluorescent dye by replacing the culture medium with assay buffer
(1.times. Hanks buffered saline, 25 mM HEPES, 0.1% w/v fatty acid
free BSA (bovine serum albumin), pH 7.4) containing 1 mM probenecid
and 1.times. Calcium 5 Reagent (Molecular Devices). Cells are
incubated at 37.degree. C. for 1 hour to allow for dye uptake.
[0620] To test for antagonist activity, test compounds at a final
concentration range between 0.32 nM-10 .mu.M (diluted in assay
buffer) are added to duplicate assay wells and and allowed to
incubate for 10 minutes prior to stimulation with PK1. After
incubation with test compounds the assay plate is placed in a FLIPR
Tetra (Molecular Devices) and PK1 (diluted in assay buffer) is
added at the determined EC80 concentration (final).
Ligand-dependent changes in intracellular calcium levels are
determined by measuring changes in fluorescence of the dye at 525
nM following excitation at 485 nM. Readings from wells that do not
contain antagonist enable percentage inhibition curves to be
plotted using 4-parameter fit algorithm and IC.sub.50 values are
calculated for each test compound. A minimum of two IC.sub.50
values determined from independent assays are generated for each
compound.
[0621] Results
TABLE-US-00001 Compound of Compound of Example No. Mean IC.sub.50
(.mu.M) Example No. Mean IC.sub.50 (.mu.M) 1 0.32 2 0.33 3 9.06 4
1.22 5 7.46 6 1.74 7 1.82 8 1.07 9 1.08 10 0.39 11 0.94 12 0.48 13
0.76 14 0.54 15 0.33 16 1.44 17 2.59 18 2.17 19 2.69 20 1.25 21
5.34 22 1.73 23 7.41 24 7.41 25 7.86 26 3.12 27 0.91 28 1.04 29
0.48 30 2.08 31 1.62 32 1.88 33 0.51 34 0.47 35 0.29 36 1.49 37
0.92 38 1.25 39 0.40 40 3.41 41 2.39 42 >9 43 >5
[0622] Generally, the compounds tested above exhibit IC.sub.50
values less than 10 .mu.M, with the most potent compounds showing
antagonist activity at the prokineticin receptor with IC.sub.50
values <1 .mu.M. Accordingly, the compounds of the invention are
expected to be useful in the prevention or treatment of conditions
in which prokineticin receptor modulation is implicated.
* * * * *